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PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND

Dissertations in Health Sciences

ISBN 978-952-61-2402-5ISSN 1798-5706



BUSHRA IMTIAZ

HORMONE THERAPY AND THE RISK OF DEMENTIA, COGNITIVE DECLINE AND ALZHEIMER’S DISEASE

Depletion of estrogen and progesterone at menopause may predispose to cognitive decline and Alzheimer’s disease (AD).

Hormone therapy (HT) has been suggested to prevent or delay this. The findings from

previous studies have been inconsistent. AD-HT association is a complex scenario and is subjected to various genetic and lifestyle factors. This thesis explored the direction of

association between HT, AD, and cognition in two nation-wide case-control studies and two

longitudinal cohort studies.

BUSHRA IMTIAZ

Hormone Therapy and the Risk of Dementia,

Cognitive Decline and Alzheimer’s disease

BUSHRA IMTIAZ

Hormone Therapy and the Risk of Dementia,

Cognitive Decline and Alzheimer’s disease

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for

public examination in Auditorium CA100, Canthia building of the University of Eastern Finland,

Kuopio, on Friday, January 20th 2017, at 12 noon

Publications of the University of Eastern Finland


Number 397

Institute of Clinical Medicine-Neurology

School of Medicine, Faculty of Health Sciences

University of Eastern Finland

Kuopio

2017

GRANO

Jyväskylä, 2017

Series Editors:

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine

Faculty of Health Sciences

Professor Hannele Turunen, Ph.D.

Department of Nursing Science


Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology


Associate Professor (Tenure Track) Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences


Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy)

School of Pharmacy


Distributor:


Kuopio Campus Library

P.O.Box 1627

FI-70211 Kuopio, Finland

http://www.uef.fi/kirjasto

ISBN (print): 978-952-61-2402-5

ISBN (pdf): 978-952-61-2403-2

ISSN (print): 1798-5706

ISSN (pdf): 1798-5714

ISSN-L: 1798-5706

III

Author’s address: Department of Neurology, Institute of Clinical Medicine, School of Medicine


KUOPIO

FINLAND

Supervisors: Professor Hilkka Soininen, M.D., Ph.D.

Department of Neurology, Institute of Clinical Medicine, School of Medicine


KUOPIO

FINLAND

Professor Miia Kivipelto, M.D., Ph.D.

Department of Neurology, Institute of Clinical Medicine, School of Medicine


KUOPIO

FINLAND

Center for Alzheimer Research, Division for Neurogeriatrics

Department of Neurobiology, Care Sciences and Society

Karolinska Institutet

STOCKHOLM

SWEDEN

Assistant Professor Anna-Maija Tolppanen, PhD.

Faculty of Health Sciences, Department of Pharmacy


KUOPIO

FINLAND

Reviewers: Professor Pirkko Härkönen, M.D., Ph.D.

Institute of Biomedicine, Cell Biology and Anatomy

University of Turku

TURKU

FINLAND

Professor Kaisu Pitkälä, M.D., Ph.D.

Department of General Practice and Primary Health Care

University of Helsinki

HELSINKI

FINLAND

Opponent: Docent Kati Juva, M.D., Ph.D.

Division on Psychiatry

Helsinki University Hospital

HELSINKI

FINLAND

V

Imtiaz Bushra

Hormone Therapy and the Risk of Dementia, Cognitive Decline and Alzheimer’s disease

University of Eastern Finland, Faculty of Health Sciences, 2017

Publications of the University of Eastern Finland. Dissertations in Health Sciences 397. 2017. 88 p.

ISBN (print): 978-952-61-2402-5

ISBN (pdf): 978-952-61-2403-2

ISSN (print): 1798-5706

ISSN (pdf): 1798-5714

ISSN-L: 1798-5706

ABSTRACT

The depletion of female sex steroid hormones occurring at menopause (natural/induced) might expose women to an increased risk of dementia, cognitive decline, and Alzheimer’s disease (AD). The availability of sex steroid hormone receptors (estrogen and progesterone) in wide areas of the brain may represent a biologically plausible mechanism for the higher AD risk in females after they pass through menopause. Findings from previous observational studies and clinical trials of the association between AD and hormone therapy (HT) use are ambiguous. This thesis comprises four research articles, two of which (1 & 4) are register based nationwide case-control studies while the other two (2 & 3) are longitudinal cohort studies. Register based studies are based on data from the Medicine and Alzheimer’s disease (MEDALZ) cohort with clinically verified AD diagnosis from 1999-2005 for study 1 (n of matched case control pairs = 19,043) and from 2005-2011 for study 4 (n of AD cases = 46,117 and n of controls= 184,463). Kuopio Osteoporosis Risk factors and Prevention (OSTPRE) cohort (n = 8195) and Cardiovascular Risk Factors, Aging and Dementia (CAIDE) cohort (n = 731) comprise the study population for studies 2 and 3 respectively. The mean follow-up time for study 1 was from 1986-2005; in study 4, it was from 1995-2011. The mean follow-up time for study 2 was 20 years; for study 3, it was 8.3 years. The main outcome for studies 1, 2 and 4 was probable AD based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association (NINCS-ADRDA) criteria; this was extracted from the Finnish special reimbursement register, while for study 3, the main outcome was the cognitive status measured at baseline (1998) and follow-up (2005). The use of HT was the main exposure in studies 2, 3 and 4 whereas gynecological surgeries (oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy) were the main exposure in study 1. Data on surgical procedures was taken from the hospital discharge register while register-based data on HT use was collected from 1995 onwards from the prescription register for studies 2, 3, and 4 along with self-reported use of HT in studies 2 and 3. The majority of women in all four studies were postmenopausal with respect to the use of HT and status of surgery. Postmenopausal surgical removal of ovaries or uterus was not a significant predictor of AD irrespective of HT use and indication for surgery. Moreover, the long term use of postmenopausal HT was protective against AD independent of surgical status (study 1). Overall postmenopausal HT use was not significantly related to AD risk (studies 2, 4) or cognitive decline (study 3) unless the use of estrogen HT exceeded over 10 years, in that case, estrogen HT was protective against AD (studies 2, 4). The results from this thesis indicate that the association of gynecological surgeries and HT with the risk of AD and cognitive decline depend upon the time of surgery with respect to the onset of menopause and duration of HT use. The protective association between longer duration of HT use with AD indirectly favors the critical window and healthy cell theories, where the effect of HT use depends upon the health status of neurons at baseline. One

VI

promising avenue for future AD studies would involve clarifying the association of short-term HT use around menopause with late-onset AD and the use of brain-specific selective estrogen receptor modulators (SERM) which spare peripheral estrogen receptors to avoid estrogen-related peripheral adverse effects. National Library of Medicine Classification: WT 155, WM 220, WP 580, WP 522, WP 468, WP 530

Medical Subjects Headings: Dementia; Alzheimer’s disease; Menopause; Estrogen; Progesterone; Hormone

therapy; Cognitive decline; Oophorectomy; Hysterectomy; Hysterectomy with bilateral oophorectomy

VIII

Imtiaz Bushra

Hormone Therapy and the Risk of Dementia, Cognitive Decline and Alzheimer’s disease

Itä-Suomen yliopisto, terveystieteiden tiedekunta, 2017

Publications of the University of Eastern Finland. Dissertations in Health Sciences 397. 2017. 88 s.

ISBN (print): 978-952-61-2402-5

ISBN (pdf): 978-952-61-2403-2

ISSN (print): 1798-5706

ISSN (pdf): 1798-5714

ISSN-L: 1798-5706

TIIVISTELMÄ: Naisten estrogeeni- ja progesteronitasot laskevat vaihdevuosien aikana. Vaihdevuodet ovat useimmin luonnolliset, mutta voivat johtua myös kohdun ja munasarjojen poistosta. Tämä hormonaalinen muutos yhdessä aivoissa sijaitsevien estrogeeni- ja progesteronireseptoreiden kanssa voivat selittää naisten miehiä suuremman alttiuden tiedollisten toimintojen alenemiselle tai muistisairauksille, kuten dementian yleisin muoto Alzheimerin tauti. Tätä hypoteesia tukee myös se, että aivojen useilla alueilla on estrogeeni- ja progesteronireseptoreja. Aiempien hormonihoitojen ja Alzheimerin taudin yhteyttä selvittäneiden havainnoivien tutkimusten ja satunnaistettujen kontrolloitujen kokeiden löydökset eivät kuitenkaan ole olleet yksiselitteisiä. Tämä väitöskirja koostuu neljästä osatyöstä, joista kaksi (1 & 4) pohjautuu valtakunnallisiin rekisteripohjaisiin tapaus-verrokki tutkimuksiin ja kaksi (2 & 3) pitkittäisiin kohorttitutkimuksiin. Osatyöt 1 ja 4 perustuvat Medicine and Alzheimer disease (MEDALZ)-tutkimuksiin, joissa osatyössä 1 olivat mukana kaikki 31.12.2005 elossa olleet suomalaiset, joilla oli kliinisesti varmennettu todennäköisen Alzheimerin taudin diagnoosi (19043 tapausta ja 19043 verrokkia) ja osatyössä 4 kaikki ne, jotka saivat saman diagnoosin vuosina 2005–2011 (46117 tapausta ja 184463 verrokkia). Osatyössä 2 käytettiin aineistoa Kuopio Osteoporosis Risk Factors and Prevention (OSTPRE)-tutkimuksesta (n=8195) ja osatyössä 3 Cardiovascular Risk Factors, Aging, and Dementia (CAIDE)-tutkimuksesta (n= 731). Osatöissä 1, 2 ja 4 päätetapahtumana oli todennäköinen Alzheimerin taudin diagnoosi perustuen Diagnostic and Statistical Manual of Mental Disorders- (DSM-IV) ja National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association- (NINCS-ADRDA) kriteeristöihin. Diagnoosit poimittiin erityiskorvausoikeusrekisteristä. Osatyössä 3 tutkittiin tiedollisten toimintojen alenemista eri osa-alueilla kahdeksan vuoden seurannan aikana. Osatyössä 1 (seuranta-aika 1995–2005) tutkittiin kohdun ja/tai munasarjojen poistoa Alzheimerin taudin riskitekijänä ja sitä, selittyykö yhteys hormoniihoidon käytöllä. Osatöissä 2-4 tutkittiin hormonihoidon yhteyttä tiedollisten toimintojen alenemaan ja Alzheimerin tautiin. Tieto kohdun ja/tai munasarjojen poistosta poimittiin hoitoilmoitusrekisteristä ja hormonihoidon käyttö osatöissä 2-4 reseptirekisteristä. Lisäksi tieto hormonihoidon käytöstä kerättiin kyselylomakkein osatöissä 2 ja 3. Kaikissa neljässä osatyössä naiset olivat pääosin vaihdevuosi-iän ohittaneita. Osatyössä 2 seuranta-aika oli 20 vuotta, osatyössä 3 keskimäärin 8.3 vuotta ja osatyössä 4 1995–2011. Kohdun ja/tai munasarjojen poisto vaihdevuosi-iän jälkeen ei ollut merkittävä Alzheimerin taudin riskitekijä. Tulokset olivat samanlaiset riippumatta hormonihoidosta ja kirurgian indikaatioista. Osatyössä 1 hormonihoitoa pitkään käyttäneillä oli pienempi Alzheimerin taudin riski kuin niillä, jotka eivät olleet käyttäneet hormonihoitoa, riippumatta siitä oliko heille tehty kohdun ja/tai munasarjojen poisto. Hormonihoitoa käyttäneiden naisten Alzheimerin taudin riski (osatyöt 2 ja 4) sekä tiedollisten toimintojen aleneminen (osatyö 3) olivat yhtä suuria kuin niillä, jotka eivät käyttäneet hormonihoitoa. Osatöissä 2 ja 4 havaittiin kuitenkin, että yli 10 vuotta hormonihoitoa käyttäneillä oli pienempi Alzheimerin taudin riski.

IX

Tämän väitöskirjan tulosten perusteella kohdun ja/tai munasarjojen poiston ja hormonihoidon sekä tiedollisten toimintojen alenemisen ja muistisairauksien välinen yhteys riippuu hormonihoidon kestosta sekä siitä, onko toimenpiteet tehty vaihdevuosi-iän jälkeen. Pitkäkestoisen hormonihoidon yhteys pienempään Alzheimerin taudin riskiin voi selittyä kriittisen aikaikkunan teorialla. Jatkossa olisikin tärkeä tutkia vaihdevuosiin ajoittuvaa lyhytkestoista hormonihoitoa sekä selektiivisten estrogeenireseptoriin vaikuttavien modulaatoreiden (SERM) kohdentamista aivoihin. Luokitus: WT 155, WM 220, WP 580, WP 522, WP 468, WP 530

Yleinen Suomalainen asiasanasto: Dementia; Alzheimerin tauti; Menopaussi; Estrogeeni; Progesteroni;

Hormonihoito; kognitio; Munasarjojen poisto; Kohdunpoisto

XII

To My Family

XIV

Acknowledgements

This Ph.D. thesis was completed in the Institute of Clinical Medicine, Department of Neurology, Faculty of Health Sciences, Kuopio, University of Eastern Finland under the Doctoral Program of Molecular Medicine. Firstly, I will like to express my immense gratitude to Professor Hilkka Soininen, M.D., Ph.D., my principal supervisor and mentor, for believing in me and providing me with an opportunity to prove myself. Her clear vision, quick responses, support, and expert opinions were the fuel that powered me through these years. I want to thank from bottom of my heart my secondary supervisors Professor Miia Kivipelto M.D. Ph.D. and Associate Professor Anna-Maija Tolppanen Ph.D. for their expert guidance and invaluable contributions towards completion of my doctoral research. Anna-Maija Tolppanen, I cannot thank you enough for all the hard work and encouragement you have poured into my research to make it better in so many ways. Your to-the-point and timely responses have always left me in awe. I found a friend in you who was always there to help me whenever I needed it. I sincerely thank all co-authors of my publications (in alphabetical order) Anna-Mari Heikkinen, Antti Tanskanen, Alina Solomon, Heidi Taipale, Heikki Kröger, Jari Tiihonen, Miia Tiihonen, Marjo Tuppurainen, Sirpa Hartikainen andToni Rikkonen for their useful insights, comments and critique. All of them are very competent and I have learnt a lot from them. I want to especially thank Associate Professor Alina Solomon M.D. Ph.D. for her deep concern, critical advice and brief but stimulating, meetings to improve my morale and knowledge alike. My warmest thanks goes to the pre-examiners of this thesis, Professor Kaisu Pitkälä, M.D., Ph.D. and Professor Pirkko Härkkönen, M.D., Ph.D. for their in-depth critical comments and suggestions, which improved my thesis considerably. I express my gratitude to Docent Kati Juva M.D., Ph.D. for agreeing to act as my opponent at the public examination of this Ph.D. thesis. I extend my thanks to Esa Koivisto for all technical help, Mari Tikkanen for travel and grant-related advices, and Arja Afflekt for her expert opinions regarding official documentation towards completion of my Ph.D. work. My sincere thanks goes to Ewen MacDonald Ph.D. for the excellent linguistic revision of the thesis. I want to acknowledge all my colleagues and office mates for their support, encouragement, and the creation of such a friendly working environment. Thank you Anna Rosenberg for helping me with the Finnish language, random things, and for daily friendly chit-chat. Many thanks to Marjo Eskelinen for her advice whenever I needed it. I owe special thanks to my colleague and best friend Ruth Stephens for everything whether it was just gossip, work-related discussions, family and social gatherings, we really excelled in all together. Thank you Olli Jääskeläinen for coffee breaks to wake-up our work routines. I will miss you all a lot. My last set of thanks is for my amazing family without whom I am nothing. My special thanks to my parents who stood by me through thick and thin. It’s not a matter of just four years of Ph.D., it’s a span of decades of their hard work to enable me to achieve my goals. Their vision is my target and their pride is my aim. I salute my mother for being such a unique and inspiring role model in all spheres of life. Her encouragemet, support and understanding towards me is precious and cannot be described in words. I want to express my heartiest gratitude towards my motherly Aunt Shahida Nasreen and fatherly Uncle Tahir Ijaz, you are part of my soul and no picture of mine is complete without both of you. I extend my warmest thanks to my loving and caring siblings namely Nomita, Ali, Tehreem, Shahnawaz, Haider, Alina and my dear sister-in-law and friend Zahra, for their understanding, support and confidence in me, you guys rock and I love you all.

XV

I cannot thank enough my dearest husband Ali Hussain for his support, love, understanding and respect towards me. I remember the day when I embarked on this Ph.D. journey leaving a three years old daughter and a three months old newborn son at home. It was not easy at all but Ali believed in me more than I believed in myself and encouraged me to pursue my career as he knew it was equally important to me. We did it together and now it seems as if four years flew in a flash. I am thankful and humbled for our lovely kids, Jannat and Hashim, for their sunshine, warmth, and unconditional love and for being the best children that any parent could ever hope for. I would also like to thank all of my Pakistani community in Kuopio for arranging interesting parties which enabled me to maintain my sanity throughout these years. I am the most grateful to the Almighty for all His blessings and favors. Lastly, I would like to thank all the funding sources during my Ph.D. work namely University of Eastern Finland, Doctoral Program in Molecular Medicine, and Finnish Cultural Foundation. Kuopio, January 2017 Bushra Imtiaz

XVI

List of the original publications

This dissertation is based on the following original publications:

I Imtiaz B, Tuppurainen M, Tiihonen M, Kivipelto M, Soininen H, Hartikainen S,

Tolppanen AM. Oophorectomy, hysterectomy, and risk of Alzheimer's disease: a

nationwide Case-Control study.

J Alzheimers Dis. 2014; 42(2):575-81. Doi: 10.3233/JAD-140336.

II Imtiaz B, Tuppurainen M, Rikkonen T, Kivipelto M, Soininen H, Kröger H,

Tolppanen AM. Post-menopausal hormone therapy and risk of Alzheimer’s disease:

a prospective cohort study (Accepted in Neurology)

III Imtiaz B, Tolppanen AM, Solomon A, Soininen H, Kivipelto M. Estradiol and

cognition in the cardiovascular risk factors, aging, and dementia (CAIDE) cohort

study. J Alzheimers Dis. 2016 Dec 9. [Epub ahead of print]

IV Imtiaz B, Taipale H, Tanskanen A, Tiihonen M, Kivipelto M, Heikkinen AM,

Tiihonen J, Soininen H, Hartikainen S, Tolppanen AM. Risk of Alzheimer’s disease

among postmenopausal hormone therapy users in a nation-wide case-control study.

(Submitted for publication)

The publications were adapted with the permission of the copyright owners.

XVIII

Contents

1 INTRODUCTION………………………………………………………………………………...1

2 REVIEW OF THE LITERATURE………………………………………………………………..2

2.1 Cognition………………………………………………………………………………………..2

2.2 Dementia………………………………………………………………………………………..2

2.2.1 Causes and symptoms of dementia…………………………………………………….3

2.3 Alzheimer's disease………………………………………………………………………….…4

2.3.1Diagnostic criteria for Alzheimer's disease………………..……………………………5

2.3.2 Biomarkers of Alzheimer's disease…………….………………………………………..6

2.3.3 Midlife risk and protective factors of Alzheimer's disease …………………………..8

2.3.4 Sex and gender based dimorphism in brain and Alzheimer's disease………….…10

2.4 Female sex steroid hormones……………………………………………………………..…11

2.4.1 Estrogens and progesterone…………………………………………………………….12

2.4.2 Mechanisms of neuroprotective effects of estrogen and progesterone…………….12

2.4.3 Sex steroid hormones and aging brain ………………………………………………..14

2.4.4 Types of commercially available hormone therapy and their implications………15

2.5 Menopause…………………………………………………………………………………….17

2.5.1 Types and stages of menopause………………………………………………………17

2.5.2 Short-term and long-term implications of menopause……………….……………..18

2.6 Hormone therapy and risk of Alzheimer's disease and dementia……………………….18

2.6.1 Clinical trials…………………………………………………………………………….19

2.6.2 Observational studies…………………………………………………………………..25

2.6.3 Surgical menopause and hormone therapy and Alzheimer's disease……………..31

3 AIMS OF THE STUDY…………………………………………………….................................34

4 SUBJECTS AND METHODS…………………………………………………………………..35

4.1 Medicine and Alzheimer's disease (MEDALZ) study (Study 1 and 4)…………………..35

4.1.1 Study population and design…………………………………………………………...35

4.1.2 Exposure data……………………………………………………………………………35

4.1.3 Outcome data…………………………………………………………………………….37

4.1.4 Covariables………………………………………………………………………...…….37

4.2 Kuopio Osteoporosis Risk Factors and Prevention (OSTPRE) cohort (Study 2)………..38

4.2.1 Study population and design…………………………………………………………..38

4.2.2 Exposure data……………………………………………………………………………40

4.2.3 Outcome data…………………………………………………………………………….40

4.2.4 Covariables……………………………………………………………………………....40

4.3 Cardiovascular Risk Factors, Aging and Dementia (CAIDE) cohort (Study 3)……….....41

4.3.1 Study population and design……………………………………………………….….41

4.3.2 Exposure data……………………………………………………………………………42

4.3.3 Outcome data………………………………………………………………………….…42

4.3.4 Covariables………………………………………………………………………………42

4.4 Statistical analyses……………………………………………………………………….……43

4.4.1 Study 1……………………………………………………………………………………43

4.4.2 Study 2……………………………………………………………………………………43

4.4.3 Study 3……………………………………………………………………………………43

XIX

4.4.4 Study 4……………………………………………………………………………………44

5 RESULTS……………………………………………………………………………………….....45

5.1 Baseline characteristics of study population……………………………………………….45

5.2 Oophorectomy, hysterectomy, radical hysterectomy and Alzheimer's disease …..…...48

5.3 Hormone therapy use and Alzheimer's disease ……………………….………………….49

5.4 Hormone therapy and cognitive decline……………………………………………………51

6 DISCUSSION…………………………………………………………………………………….53

6.1 Oophorectomy, hysterectomy, and risk of Alzheimer's disease (Study 1)………………53

6.2 Postmenopausal hormone therapy use and risk of Alzheimer's disease and dementia

(Studies 1, 2, 4)…………………………………………………………………………………….54

6.2.1 Use of hormone therapy in relation to oophorectomy and hysterectomy (Study

1)…….……………………………………………………………………………………………...54

6.2.2 Postmenopausal hormone therapy and risk of Alzheimer's disease and dementia

(Studies 2, 4)……………………………………………………………………………………….55

6.3 Use of hormone therapy and cognitive decline (Study 3)…………………………………56

6.4 Methodological considerations (all studies)………………………………………………..57

7 CONCLUSIONS…………………………………………………………………………………60

8 FUTURE PERSPECTIVES……………………………………………………………………...61

9 REFERENCES…………………………………………………………………………………….63 ORIGINAL PUBLICATIONS (I-IV)

XX

Abbreviations

Aβ amyloid beta protein AD Alzheimer’s disease ADRDA Alzheimer’s disease and

related disorders association APP amyloid precursor protein APOE apolipoprotein E (gene) ATC Anatomical Therapeutic

Chemical BMI body mass index Bcl-2 B cell lymphoma 2 CAIDE Cardiovascular Risk Factors,

Aging and Dementia CEE conjugated equine estrogens CERAD Consortium to Establish a

Registry for Alzheimer’s disease

CI confidence interval CSF cerebrospinal fluid CT computerized tomography DSM-IV Diagnostic and Statistical

Manual of Mental Disorders 4th edition

DLB Dementia with Lewy bodies ELITE Early versus Late Intervention

Trial with Estradiol FINMONICA Finnish Multinational

Monitoring of Trends and Determinants in Cardiovascular disease

FTLD frontotemporal lobar degeneration

G03C estrogen G03D progesterone G03F estrogen and progesterone in

combination G03X other sex hormones and

modulators of genital system HR hazards ratio HRQOL Health-related quality of life HT hormone therapy ICEE index of cumulative estrogen

exposure ICD International Classification of

Diseases IWG International Working Group KEEPS-cog Kronos Early Estrogen

Prevention Study-cognitive and affective study

MEDALZ Medicine and Alzheimer’s disease study

MCI mild cognitive impairment MMSE mini-mental scale

examination MPA medroxy progesterone acetate MRI magnetic resonance imaging 3MS modified mini-mental scale NA not available NIA-AA National Institute of Aging

and Alzheimer’s Association NINCS-ADRDA National Institute of

Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association

NOMESCO Nordic Medico-Statistical Committee’s Classification of Surgical Procedures

NSAIDS Non-steroidal anti-inflammatory drugs

OSTPRE Osteoporosis Risk Factor and Prevention

OR odds ratio PDD Parkinson’s disease dementia PET positron emission

tomography PUFA poly-unsaturated fatty acids RCT randomized controlled trial SERM selective estrogen receptor

modulators TICS-m Telephone interview of

cognitive status-modified TSEC tissue specific estrogen

complex USA United States of America VaD vascular dementia VMS vasomotor symptoms WHIMS Women’s Health Initiative

Memory Study

1

1 Introduction

Dementia is a syndrome characterized by progressive impairment in memory and other

cognitive abilities, ultimately interfering with daily life activities. Dementia is attributable

to Alzheimer’s disease (AD) in 60-80% of cases and in view of its health care and care-giving

costs, many recent interventions have been aimed towards prevention, delay in onset, and

to slow down progression of AD (Alzheimer's Association 2016). The world-wide

prevalence of dementia in 2015 was 46.8 million, a value which is projected to double every

20 years leading to an estimated total of 131.5 million AD patients in 2050. Another way of

assessing this change is that by 2030, AD will be a trillion dollar disease compared to the

billion dollar disease it is at the moment (Alzheimer's disease International 2015).

Recent guidelines for AD diagnosis emphasize the importance of the identification of the

pre-clinical stage of dementia based on clinical presentation and biomarker findings

(cerebrospinal fluid (CSF), neuroimaging) in order to target preventive strategies for those

at risk of dementia, since it is thought that they will benefit most from effective therapeutics

(Dubois et al. 2010, Dubois et al. 2014). Research on the pathogenesis of AD has identified

multiple modifiable midlife risk factors, thus providing a window of opportunity for

prevention (Barnes and Lee 2011).

In the United States (US), two thirds of all AD cases are women (Hebert et al., 2013). The

higher risk of AD in women might be due to their longer life span (Seshadri et al., 1997) or

to the depletion of sex-steroid hormones at menopause (Vest and Pike 2013). This thesis

focuses on the interaction between postmenopausal hormone therapy (HT) use and AD, and

also investigates the cognitive decline in different population based studies from Finland.

Neuroprotective effects of estrogen are well-established in basic science and animal studies

but findings from clinical trials and observational studies have been inconsistent (Brinton,

2008a, Zandi et al., 2002a, Bove et al., 2014, Shumaker et al., 2013, Espeland et al., 2004,

Marinho et al., 2008). The presence of estrogen receptors in those areas of brain which are

involved in AD pathology, provide support for a biologically plausible mechanism to

account for the potential beneficial effects of HT to prevent this debilitating illness.

The present thesis comprises two case-control and two cohort studies and is intended to

evaluate the effect of postmenopausal HT on late-life cognitive decline and AD. One study

focuses on the association between AD and gynecological surgeries (oophorectomy,

hysterectomy, and hysterectomy with bilateral oophorectomy). The studies in this thesis

have evaluated various lifestyle, socioeconomic, and demographic variables in order to

account for potential bias and confounding in the AD-HT relationship.

2

2 Review of the literature

2.1 COGNITION

Cognition comprises a set of mental abilities needed to perform a wide range of functions i.e. from the simplest to the most difficult task to be tackled. Cognition has been categorized into different domains depending upon the brain areas involved in their execution. Cognitive domains can be subdivided into perception, attention, memory, motor skills, language, visuospatial abilities, and executive functions (Michelon Pascale, 2006). Aging itself is associated with a subtle cognitive decline but the cognitive decline associated with normal aging is different from the cognitive changes occurring in the preclinical stages of AD. Identification of AD-specific cognitive domains and their assessment is used in diagnostics of AD when the disease is in its initial stages. A decline in episodic memory of hippocampal type, which is not corrected by cueing recall, has been added to the diagnostic criteria in recent guidelines (Dubois et al., 2007). Other cognitive domains affected by aging are verbal memory (Marquis et al., 2002), working memory (Small et al., 1999), attention (Stankov, 1988), and visual perception (Koss et al., 1991). The presence of estrogen receptors in hippocampus, frontal lobes, and basal forebrain where most of these cognitive domains are controlled, represents a plausible connection between sex steroid hormones and cognitive process.

2.2 DEMENTIA

Dementia is an umbrella term characterized mainly by loss of memory and other mental abilities, ultimately leading to impairments in activities of daily living. Its incidence and health- and care-giving related costs are expected to increase at an alarming rate in the coming decades (Wimo et al., 2013). Life expectancy has considerably increased during the last century, thus increasing the prevalence and incidence of chronic illnesses such as dementia. The regional prevalence of dementia ranges from 4.6% in Central Europe to 8.7% in North Africa and the Middle East. The expected prevalence of dementia has been predicted to be much lower in high income countries compared to low and middle income countries where the prevalence is anticipated to increase from 58% to 68% between 2015 and 2050 (Alzheimer's disease International 2015). Dementia not only affects the diseased person but also the whole family in terms of care-giving and financial management. From a wider perspective, it affects entire societies and countries in terms of arranging health care services and increasing the burden of disease due to disabilities (Wimo et al., 2010, Wimo et al., 2013). Currently, the worldwide costs of dementia are estimated to be 818 billion United States dollars, and dementia is expected to become a trillion dollar disease by 2030 (Wimo et al., 2016). Considering the continuous increase in the ageing population, dementia has been declared a global health priority by the United States, the Group of 7, and World Health Organization who have issued a common agenda of preventing and treating this debilitating disease through increased funding for its research and raising awareness through various public health and societal platforms at community levels (Wortmann 2012, Wimo et al., 2016).

3

2.2.1 Causes and symptoms of dementia The most important symptoms of dementia include memory loss, difficulty in learning new information, language problems, and impairment in other cognitive domains namely planning, judgment, reasoning, organizing, and execution of complex tasks. Considering the complexity of the structure and function of the human brain, a direct diagnosis of dementia is always difficult and exclusion of other differential diagnoses is required in order to reach a definite diagnosis, in contrast to other chronic illnesses e.g. cardiovascular disease and cancer where direct diagnosis is relatively straightforward.

Figure 1: Etiologies of dementia with their subtypes (Alzheimer's Association 2016)

The different etiologies of dementia are summarized in Figure 1. AD is the most important

type of dementia accounting for 60-80% of cases, and it is characterized by impaired

memory as its primary symptom, with difficulties in memorizing newly learnt information

(Wilson et al., 2012). The second most common (15-20%) type of dementia is vascular

dementia (VaD) with initial symptoms of impaired judgement, planning, decision making,

as well as motor functions being affected due to blockage or rupture of brain vessels leading

to infarcts and hemorrhage. VaD is a heterogeneous condition with several subtypes

including large vessel VaD (multi-infarct dementia, strategic infarct dementia); ischemic

hypoperfusive VaD (cortical or subcortical); small-vessel VaD; and hemorrhagic VaD

(Roman et al., 2002). Other common types of dementia are dementia with Lewy bodies

(DLB) and Frontotemporal Lobar Dementia (FTLD) dementia, and Parkinson’s disease

dementia (PDD). DLB and FTLD account for 10-15 % and 10% of disease burden

respectively. DLB and Parkinson’s disease dementia (PDD) are characterized by the

Dementia [Alzheimer’s

association, 2016]

Alzheimer’s dementia (AD)

60–80 %

Vascular dementia (VaD)

15–20 %

Dementia with Lewy bodies

(DLB) 10-15 %

Parkinson’s disease dementia

(PDD)

Frontotemporal Lobar

Degeneration (FTLD) 10 %

Normal pressure hydrocephalus

(5 %)

Almost half have only AD pathology

Others have mixed pathology

Multi-infarct dementia

Strategic infarct dementia

Ischemic-hypoperfusive dementia

Haemorrhagic vascular dementia

Others

Corticobasal degeneration

Progressive supranuclear palsy

Pick’s disease

Behavioral variant FTLD

Creutzfeldt Jakob disease

Huntington’s disease

Wernicke-Korsakoff Syndrome

4

presence of the abnormal accumulation of alpha synuclein protein (Lewy bodies) in neurons

(Spillantini et al., 1998, McKeith 2002). FTLD presents with spared memory in the early

stages (unlike AD), but instead with marked changes in personality and behavior

(Rabinovici and Miller 2010). There are also other causes of dementia, e.g. dementia due to

normal pressure hydrocephalus; Creutzfeldt Jakob disease related dementia due to a

misfolded protein (prion) in brain; Huntington’s disease caused by a defective gene on

chromosome 4; and Wernicke-Korsakoff syndrome, a chronic memory disorder caused by

severe deficiency of thiamine (vitamin B-1) due to nutritional deficiency and alcoholism

(Geldmacher and Whitehouse 1996, Zubaran et al., 1997). Mixed dementia is the type of

dementia where more than a single cause of dementia is encountered. Around half of AD

dementias have a mixed pathology e.g. AD+VaD, AD+DLB, AD+DLB+VaD; these are more

frequent among the oldest old i.e. >85 years (Jellinger and Attems 2007).

2.3 ALZHEIMER’S DISEASE

AD is a neurodegenerative disorder which is not a part of normal aging. Its symptoms

develop gradually and worsen over time, resulting in impairment of activities of daily living

and ultimately death. In the US alone, 5.4 million people of all ages had been diagnosed

with AD in 2016, 5.2 million of them were aged 65 years and older and this number will rise

as the US older population (>65 years) is expected to increase from 14% in 2012 to 22% in

2050 (Alzheimer's Association 2016).

Histopathologically, AD is characterized by extracellular deposition of amyloid protein

(Aβ) plaques and intracellular tau protein tangles. Previous studies have clarified the

association between AD and neurofibrillary tangles (Bennett et al., 2004) and brain

amyloidosis and AD (Mormino et al., 2009). Moreover, brain amyloid deposition has been

linked with decreased brain volume (Oh et al., 2011, Fjell et al., 2010, Dickerson et al., 2009),

disruption of functional networks (Sperling et al. 2009, Sheline et al. 2010, Hedden et al.

2009), and an increased risk of cognitive decline and progression to dementia in the future

(Fagan et al., 2007, Li et al., 2007, Resnick et al., 2010) in cognitively normal older people.

These findings emphasize the role of brain amyloid and tau pathology in AD diagnosis. AD

related pathology primarily involves brain areas involved with memory and it then spreads

to other brain regions, thus evoking varying symptoms with different severities.

AD can be sporadic or late onset among >65 year olds as well as familial or early onset

among younger people i.e. <65 years of age. Investigations into the familial form of AD, also

known as monogenic AD, has helped in understanding the possible mechanisms initiating

this illness. Familial AD is caused by autosomal dominant inherited gene mutations coding

for amyloid precursor protein, presenilin 1 and presenilin 2. This kind of autosomal AD

accounts for only about 1% of all AD cases. The increased risk of AD in subjects carrying

mutations in these genes is proposed to be due to increased accumulation of amyloid

proteins (Amemori et al., 2015). Sporadic AD develops possibly due to decreased clearance

of amyloid from brain, either by carrying the Ɛ4 allele of apolipoprotein E (APOE), or being

genetically predisposed due to a family history of AD, or due to still unknown mechanisms

(Padayachee et al., 2016).

5

2.3.1 Diagnostic criteria for AD

The first AD case was diagnosed in 1906, but it was not until 1984 when the first diagnostic

criteria for AD were devised by the National Institute of Neurological and Communicative

Disorders and the Alzheimer’s disease and Related Disorders Association (NINCS-

ADRDA) workgroup; these have now been used successfully for over 27 years. According

to the NINCS-ADRDA criteria, AD could only have an amnestic presentation; it was

considered to be a clinical and pathological entity, whose diagnosis was only probable

during the subject’s lifetime; a definite diagnosis could be ascertained only after combining

amnestic presentation during the patient’s life with AD-related neuropathology at autopsy.

No intermediate stage of memory loss was defined and information on biomarkers was

lacking at that time as well as nothing being known about genetic forms. Furthermore non-

amnestic presentations of AD were not acknowledged to any significant extent (McKhann

et al., 1984).

Dementia research has recently viewed new horizons, i.e. AD pathology has been observed

in the absence of clinical symptoms (Price and Morris 1999) along with non-amnestic clinical

presentation of AD with prominent language and visuospatial abnormalities (Tang-Wai et

al., 2004, Rabinovici et al., 2008, Alladi et al., 2007). The presence of AD pathology before the

onset of clinical symptoms led to the assumption that there must be a long asymptomatic

stage between the first brain lesion and the first clinical symptom, thus raising the

importance of identifying this intermediate stage (Dubois et al., 2007, Dubois et al., 2010).

Based on recent developments, National Institute of Aging and Alzheimer’s Association

(NIA-AA) sponsored a revision of the NINCS-ADRDA criteria (Jack et al., 2011, Sperling et

al., 2011, Albert et al., 2011, McKhann G et al., 1984, McKhann et al., 2011). Moreover, an

International Working Group (IWG) revised NINCS-ADRDA criteria separately and

produced their recommendations for AD diagnosis [Dubois et al., 2014; Dubois et al., 2007;

Dubois et al., 2010].

The concept of dementia has been changed from a clinical-pathological entity (NINCS-

ADRDA) to a dual clinical-biological entity in the IWG criteria and to a pathophysiological

and clinical entity by NIA-AA. AD is now characterized as a spectrum of disease by NIA-

AA, which has different stages inherent in its pathology; pre-clinical AD, mild cognitive

impairment (MCI), and AD-dementia. Pre-clinical AD defined by NIA-AA is only intended

for research purposes at the moment. Biomarker positivity is required for diagnosis, with

evidence of AD related pathological changes not meeting the clinical criteria for MCI or

dementia. Pre-clinical AD was further categorized into 3 stages mainly based on biomarker

positivity. The reason for attempting to identify this stage is that it may provide a window

of opportunity for drug trials which might be effective at this early disease stage (Sperling

et al., 2011). MCI was defined by NIA-AA on the basis of both core clinical criteria (for

clinicians) and research criteria (for clinical trials, including biomarker evidence). The MCI

stage differs from the dementia stage mainly in its preservation of independence in activities

of daily living (Albert et al., 2011). The core clinical criteria were sufficient to diagnose

dementia due to AD in the NIA-AA guidelines. According to these criteria, dementia was

defined as a progressive cognitive decline, diagnosed through history taking and which

could not be explained due to other reasons. Moreover, the cognitive decline should be

6

sufficient to interfere significantly with activities of daily living, such as performing

complex tasks at work, at home, acquiring and retaining new information, and

deteriorations in language functions etc. Probable AD dementia as defined by NIA-AA was

the same as that defined by NINCS-ADRDA but could have an amnestic or a non-amnestic

presentation and with increased certainty among those carrying genetic mutations (amyloid

precursor proteins (APP), presenilin 1 and 2). Possible AD dementia was defined among

those having atypical AD or mixed dementia (McKhann et al., 2011).

The IWG initial guidelines identified various stages of AD including prodromal AD, typical

AD, atypical AD, AD dementia, mixed AD and the pre-clinical state of AD. These guidelines

emphasized the presence of biomarkers to diagnose different states of AD (Dubois et al.,

2010). However, in their revised criteria, IWG emphasized the core clinical criteria in the

diagnosis AD, so that their criteria could be used effectively in both clinical and research

settings. In the revised guideline’s core clinical criteria, typical AD was defined as an

amnestic syndrome of the hippocampal type. This syndrome can be identified in clinical

settings by a decline in tests that assess effective registration of an item to be remembered

and probe response to cueing as a measure of the storage abilities and associative function

of the hippocampus. Biomarkers are a part of revised guidelines but now their purpose is

to support the diagnosis rather being compulsory as in the previous IWG guidelines. The

revised criteria also identified mixed AD, pre-clinical AD and atypical AD (Dubois et al.,

2014).

2.3.2 Biomarkers of AD

Biomarkers are biological indicators that help to diagnose a disease with certainty. AD

biomarkers were not available in 1984, when the first AD diagnostic criteria were

formulated. The recently developed AD biomarkers have helped to increase the specificity

of AD diagnosis and are included in both the IWG and NIA-AA criteria. A correlation

between AD clinical symptoms and biomarkers has been demonstrated (Jack et al., 2010,

Mormino et al., 2009, Perrin et al., 2009).

AD biomarkers are divided into two main categories: (1) biomarkers for amyloid deposition

[CSF Aβ42, Positron emission tomography amyloid imaging], (2) biomarkers of neuronal

injury [CSF total tau, phosphorylated tau, fluorodeoxyglucose positron emission

tomography imaging, single photon emission tomography perfusion imaging, functional

magnetic resonance imaging, hippocampal volume or medial temporal lobe atrophy by

volumetric measures or visual rating].

Diagnostic guidelines of IWG and NIA-AA differ with respect to the use of biomarkers to

diagnose pre-clinical AD (Sperling et al., 2011, Albert et al., 2011). In NIA-AA guidelines, a

biomarker abnormality supported the AD diagnosis, but was not essentially required or

sufficient; while IWG listed certain biomarkers as being required for AD diagnosis (Dubois

et al., 2010, McKhann et al., 2011).

NIA-AA devotes equal importance to markers of Aβ deposition and neuronal injury in all

stages of AD, while in the IWG-2 criteria, the presence of both markers i.e. decreased Aβ1-42

together with high total or phosphorylated tau in CSF, is essential for the diagnosis of typical

AD (Dubois et al., 2014). Recently, the state and stage of AD have emerged as two different

7

concepts where state denotes a pathophysiological process (such as asymptomatic but at

risk of AD) and stage refers to the progression of disease in a certain state (Dubois et al.,

2016). AD has both a preclinical and a clinical stage; furthermore the clinical stage of AD

comprises the prodromal and the dementia stages. The clinical phenotype of AD can be

either typical or atypical. (Dubois et al., 2016).

Despite the major developments in biomarker identification, there is no consensus on

whether they should be required for AD diagnosis (Herrup 2010, Pimplikar et al., 2010).

Moreover, the biomarker evaluation of AD pathology needs to undergo validation and

standardization in terms of CSF collection, processing, performing quantitative assays, and

accessibility and costs (Morris et al., 2014).

According to Diagnostic and Statistical Manual of Diseases 5th edition, AD is now classified

as a major neurocognitive disorder and MCI as minor neurocognitive disorder based on the

fact that it involves both neurological functions and interference with activities of daily

living. It is true that diagnosing and labeling an individual with dementia without a definite

diagnosis can raise serious ethical issues, on the other hand, it can help undiagnosed

dementia cases who suffer from this disorder without proper care and support. Thus, their

needs may be acknowledged and appropriate care can be planned after their diagnosis.

8

2.3.3 Midlife risk and protective factors of AD

AD is nowadays considered as a continuum of disease which begins well before the

appearance of any clinical symptoms (McKhann et al., 2011). As a result, various protective

and risk factors of AD have been recognized which operate throughout the individual’s life-

span especially during midlife, thus affecting his/her likelihood of developing AD. Some of

the protective and risk factors of AD pertaining to lifestyle and sociodemographic are listed

in Figure 2 (Solomon et al., 2014a).

Risk factors of AD can be categorized into two main categories; modifiable and

unmodifiable factors. Age, genetic constitution (APOE status) and family history of AD fall

into the unmodifiable group of risk factors.

Age is the strongest predictor of AD, i.e. the risk of AD increases exponentially as the

individual gets older. The presence of the APOE Ɛ4 allele is another well-established genetic

risk factor for sporadic AD and >60% of AD cases carry at least one APOE Ɛ4 allele (Riedel

et al., 2016). Women carrying one APOE Ɛ4 allele had similar risk of AD as men homozygous

for APOE Ɛ4 (Farrer et al., 1997). The APOE gene encodes a protein which acts as a major

component for central nervous system lipoproteins and is thus involved in lipid transport

in brain (Manaye et al., 2013). The APOE ε4 isoform increases the risk of AD through

increased production of amyloid Aβ, and a decrease in dendritic spine density (Rodriguez

et al. 2013, Dumanis et al., 2009).

Another important determinant with respect to APOE ε4 status is its interaction with female

sex steroid hormones. APOE is a biological factor which associates with sex, genetic, and

lifestyle related factors (education, physical activity, smoking, occupation status, and job

situation) to alter AD-related pathology (Rocca et al., 2014b). Women homozygous for

APOE Ɛ4 were found to have lower CSF Aβ levels in a dose response manner in late onset

AD but not in early onset AD (Mehrabian et al. 2015). In females, the influence of APOE Ɛ4

presence was more pronounced on the neuropsychiatric symptoms of AD (Xing et al., 2015),

and APOE Ɛ4 carriers showed more severe amyloid pathology on positron emission

tomography than was present in non-carriers (Jack et al., 2015).

The modifiable risk factors of AD include cerebrovascular and cardiovascular risk factors,

such as obesity, smoking, alcohol intake, and high fat diet (Solomon et al., 2014a) with

higher education, social and physical activity, and doing a mentally stimulating job being

associated with a decreased risk of dementia (Wilson et al., 2007). The mechanisms through

which higher education, higher socioeconomic status, being socially active and doing a

mentally stimulating job protect from AD are possibly mediated through the increase in

cognitive and brain reserve (Wilson et al., 2010, Fotenos et al., 2008). A higher brain reserve

would enable a brain to better withstand pathological insults due to the presence of the

larger number of healthy neurons, while cognitive reserve denotes the brain’s ability to

exploit alternative networks of brain to combat the developing pathology, such as in AD

(Sperling et al., 2011). Both cognitive and brain reserve enable the brain to tolerate the initial

symptoms of dementia without showing any clinical symptoms for a longer duration of

time, but it may also lead to a more rapid decline once compensatory mechanisms stop

functioning (Fotenos et al., 2008). APOE Ɛ4 and education influence the onset of dementia

9

independently as well as interactively i.e. the risk of dementia is halved among APOE Ɛ4

carriers with high education in comparison to APOE Ɛ4 carriers with low education (Wang

et al., 2012).

Smoking, alcohol intake, low physical activity, and high fat diet etc. predispose to higher

risk of AD. These habits may promote accelerated aging of brain through metabolic and

glucose dysregulation, oxidative stress and chronic inflammation, all of which are factors

that increase the risk of AD either independently or operate through increasing the risk of

cardiovascular and cerebrovascular diseases (Arvanitakis et al., 2004, Yaffe et al., 2009,

Schmidt et al., 2002). Volunteering in any task has been associated with decreased mortality

among older people, and the underlying reason can be that volunteerism stems from

emotional wellbeing and as well as the social interactions gained by this activity (Harris and

Thoresen et al., 2005). Obesity itself is an important predictor of AD. Midlife BMI of >30 in

conjunction with high systolic blood pressure and higher total cholesterol increase the risk

of AD either through the inflammation associated with obesity or increasing the risk of the

metabolic syndrome (Kivipelto et al., 2005). Diabetes mellitus is another risk factor acting

either independently or in combination with obesity to increase the risk of AD via insulin

resistance and microvascular disease in brain. Brain insulin production may be inhibited by

peripheral hyperinsulinemia, which in turn may decrease the clearance of amyloid from the

brain (Barnes and Yaffe 2011). Moreover, adipocytes are known to secrete various hormones

(leptin, cortisol) and cytokines (tumor necrosis factor-alpha and interleukin 6) which

collectively increase the risk of AD by inducing inflammation in brain and by altering brain

beta amyloid levels (Profenno et al., 2009). An elevated serum cholesterol level is a well-

established risk factor for AD since it promotes the formation of amyloid beta in neuronal

cell membranes through the formation of cholesterol rich areas which preferentially process

APP into Aβ (Casserly and Topol 2004). High blood pressure in midlife is associated with a

higher risk of late-life dementia. Hypertension increases the risk of developing white matter

lesions, small and large vessel disease, and brain atrophy, all of which may converge and

thus link the higher risk of dementia with high blood pressure (Launer et al., 2000).

Hypertension also affects the endothelial lining of blood vessels, altering their permeability

and inducing proinflammatory and procoagulant responses in cell membranes, which in

turn may trigger the formation of neuritic plaques, a hallmark of AD (Hallenbeck 1994). A

decline in the incidence of dementia with antihypertensive drugs among older people

support the view that hypertension is a modifiable risk factor for dementia (Forette et al.,

2002, Feigin et al., 2005).

Other important factors associated with a decreased risk of AD are higher intellectual

activity, being in a relationship (marriage), which also delays AD through increasing

cognitive reserve (Vemuri et al. 2014, Sundstrom et al., 2016). In summary, preventing or

delaying the onset of AD clearly demands monitoring and modifying of midlife risk and

protective factors for AD (Solomon et al., 2013).

With regard to the several protective factors, hormone therapy (HT) holds a special place as

a potential therapeutic to prevent or delay onset of dementia in women. Considering the

longer life span of women, the menopause also marks a midlife event (mean age 51 years)

as more than one third of a woman’s life span is spent in the postmenopausal state. Thus,

10

the higher risk of AD among females than males can be associated biologically with the

decline in the amounts of sex steroid hormones (estrogen and progesterone) at menopause

(Vest and Pike 2013). The use of conjugated equine estrogens was not associated with a

cognitive decline in a recent meta-analysis, but this report did not consider other

formulations of estrogens such as estradiol. In the same meta-analysis, cognitive training

was associated with a decreased risk of cognitive decline, while current smoking and APOE

Ɛ4 genotype were associated with an increased risk of AD (Plassman et al., 2010). The

biological effectiveness of estrogen is reduced in the presence of the APOE Ɛ4 allele (Manaye

et al., 2013). It has been reported that estrogen conferred protection against cognitive decline

among APOE Ɛ4 negative women but not in APOE Ɛ4 positive women (Yaffe et al., 2000a).

This concept may also explain the higher risk of AD among women which might be

mediated through the APOE interaction with female sex per se.

Though no clear guidelines are available whether or not to use HT among postmenopausal

women as a means to prevent dementia or AD, much research has been conducted in this

field during the past two decades; there is evidence of a neuroprotective potential of HT

emerging from experiments conducted in animals as well as in observational trials. Some

discrepancies have also been seen with respect to the clinical trial findings; these will be

discussed in detail in the following chapters.

Figure 2: Risk and protective factors of AD (Solomon et al., 2014)

2.3.4 Sex based dimorphism in brain and AD

Of the 5.2 million people with AD in United States, 3.3 million (two thirds) are women

(Alzheimer's Association 2016). Similarly, in global terms, more than 60% of patients with

AD are women (Riedel et al., 2016). The higher risk of AD among women than men can be

simply attributed to their longer life span (Gao et al., 1998) but it may also be linked to

underlying sex-based dimorphism in the human brain (Woods and Tsui 2014). Sex and

RISK FACTORS

Unmodifiable

Age

Family history

APOE Ɛ4

Modifiable

Cerebrovascular risk factors

Cardiovascular risk factors

Smoking

Alcohol intake

High fat diet

PROTECTIVE FACTORS

Education

Social activities

Cognitive engagement cognitive reserve

Physical activity

Mentally stimulating job

High socioeconomic

status

Mediterranean diet

Antioxidant vitamins

NSAIDS

Statins

Hormone therapy Polyunsaturated fatty acids

11

gender have emerged as separate entities recently, where sex defines biological

characteristics such as chromosomal constitution (XX or XY), gonadal and hormonal

differences, while gender refers to cultural, psychological and social differences (access to

education, occupation) between men and women (Ristvedt 2014, Mielke et al., 2014). Thus,

identification of both sex- and gender- based risk and protective factors are critical in

understanding a chronic illness such as AD. Sexual dimorphism is driven by the levels of

the sex-specific hormones prevailing during prenatal period, adolescence, puberty, and

adulthood (Li et al., 2014) and these are governed by hormone dependent gene activations

in a sex specific manner (Nugent et al., 2012). One such example is the sex hormone

mediated language development which differs depending on whether the postnatal

hormonal surge is mediated by estrogen or testosterone (Schaadt et al., 2015).

The distinctive distributions of estrogen and androgen receptors in brain account for

differences in performance in brain tasks (Li and Singh 2014); this has been linked with

certain pathological variants; long term estrogen depletion was reported to be associated

with cognitive decline (Mielke et al., 2014); excess hormone exposure results in polycystic

ovarian syndrome in females (Nugent et al., 2012); and X-inactivation is associated with an

increased AD risk among females (Ferrari et al., 2013).

All of these mechanisms suggest that sex-specific hormones affect an individual’s likelihood

of developing AD in a variety of ways. It can be mediated through down-regulation of

estrogen receptors in hippocampus in the case of long term-estrogen depletion, thus

affecting the main area of the brain involved in neuroprotection and cognitive enhancement

(Mielke et al., 2014). There are also possible indirect pathways e.g. the higher risk of AD

among women with polycystic ovarian disease, who also have a higher risk of developing

the metabolic syndrome due to insulin resistance, higher BMI and cholesterol levels. These

metabolic changes predispose women with polycystic ovaries to a higher risk of AD

(Nugent et al. 2012). Similarly, genetic mechanisms may be involved in the higher

prevalence of AD among women, such as inactivation of the X-chromosome during

embryogenesis since this chromosome mainly carries neuroprotective genes, or it can be

due to unknown non-genetic and epigenetic mechanisms (Ferrari et al. 2013).

Moreover, sexual dimorphism in brain is associated with a higher incidence of AD among

women through sex-specific white matter lesions (Gallart-Palau et al., 2016) and an

increased rate of cognitive decline among females than males (Laws et al., 2016, Koran et

al., 2016). These sex-specific associations involve a complex interplay between hormonal,

genetic, and environmental factors (Carter et al., 2012).

2.4 FEMALE SEX STEROID HORMONES

Primary female sex-specific hormones are estrogen and progesterone. They are small,

hydrophobic molecules carried through serum globulin in the bloodstream. Sex hormone

production is regulated by the hypothalamic pituitary gonadal axis through tightly

controlled hormonal and neural signals between the central nervous system, the pituitary

and the ovaries respectively. The following hormones are part of the hypothalamic pituitary

gonadal axis: 1. Gonadotrophin-releasing hormone; 2. Gonadotrophins i.e. luteinizing

12

hormone and follicle stimulating hormone (Henry, Norman 2014). Low levels of circulating

estrogens and progesterone trigger the release of gonadotrophin releasing hormone from

hypothalamus which then stimulates the pituitary to release follicle stimulating hormone

and luteinizing hormone, both of which act on the developing follicles to produce estrogens

and progesterone (Henry and Norman 2014, Blair et al., 2015b).

2.4.1 Estrogens and progesterone

Estrogen is produced mainly in the reproductive organs (ovaries) during reproductive life

and from non-reproductive sites (liver, brain, bone, adipose tissue, muscle, heart) before

puberty and after menopause though its level are rather low in comparison with the ovarian

estrogens. There are 3 types of estrogen endogenously present in females: estradiol (17β

estradiol), estrone, and estriol. Estradiol is the most potent and most prevalent during the

reproductive years; estrone is synthesized from adipose tissue mainly after menopause,

while estriol is prevalent during pregnancy and is produced by the placenta (Cui et al.,

2013).

Sex hormones exert their biological actions through cell and tissue specific receptors. The

concept of the estrogen receptor was proposed in the late 1950s (Jensen and Jacobson 1962)

and the estrogen receptor α was identified in the 1960s (Toft, Gorski 1966). The gene for

human estrogen receptor α was cloned in 1986 (Greene et al., 1986) and that for estrogen

receptor β was discovered in the late 1990s. Both receptors are widely distributed in brain

and body (Henry and Norman 2014).

Estrogen exerts its specific effects primarily through its nuclear receptors i.e. estrogen

receptor α or β (genomic), but also by binding to its membrane bound receptors (non-

genomic) (Hewitt et al., 2016, Blair et al., 2015b). The estrogen receptor α is primarily

expressed in reproductive organs whereas estrogen receptor β is expressed in a wide variety

of tissues. Both estrogen receptors are present in various brain regions including amygdala,

cortex, hippocampus, hypothalamus, substantia nigra, stria terminalis, and preoptic area

(Cui et al., 2013).

The other important female sex steroid hormone is progesterone, which in reproductive life

is produced in the ovaries (corpus luteum), placenta, and adrenal gland (cortex). There are

two types of receptors for progesterone, i.e. progesterone receptors A and B; the B-form of

the progesterone receptor is more potent than the A-form (Henry and Norman 2014). The

activity of the progesterone receptor is dependent on estrogen as well as the properties of

the estrogen receptor in target tissues; progesterone receptors also act as a transcription

factor similarly as the estrogen receptors. Estrogen receptors are more widely distributed

than progesterone receptors, which are limited to uterus, ovary in the periphery, but they

are also present in several areas of the brain including pituitary. The presence of

progesterone receptors throughout brain means that it should not simply be considered as

a reproductive hormone.

2.4.2 Mechanisms of neuroprotective effects of estrogen and progesterone

In vivo animal and human autopsy studies have demonstrated the wide distribution of the

estrogen receptor α throughout the hypothalamus, forebrain, and amygdala (Osterlund and

13

Hurd 2001, Mitra et al., 2003) and the estrogen receptor β in hippocampus and cerebral

cortex (Mitterling et al., 2010, Ostlund et al., 2003) emphasizing the role of estrogen in brain

functions. A brief summary of some of the neuroprotective mechanisms of estrogen and

progesterone is presented in Table 1.

Estrogen can confer neuroprotection through induction and regulation of synaptic activity

in hippocampus and the formation of excitatory synapses through N-methyl-D-aspartate

receptors (McEwen and Alves 1999, Hao et al., 2003, Jacome et al., 2016) and estrogen

receptor mediated gene transcription to regulate hippocampal function (Han et al. 2013).

Estrogen may increase synaptic plasticity whereas progesterone antagonizes this protective

effect of estrogen (Baudry et al. 2013) and increases neuronal spine density in prefrontal

cortex and hippocampus (Tang-Wai et al. 2004, Shanmugan, Epperson 2014).

Estrogen enhances hippocampal learning through neurogenesis although this may depend

upon the type, duration, and time of initiation of HT. Estrogen increases neurite growth and

synaptic plasticity among healthy neurons, but not in aged neurons which are less

responsive to estrogen. Moreover, a longer duration of naturally occurring estrogen

(estradiol) use encompassing the critical time period when neurons are still healthy is

another important factor determining the effect of HT on cognition (Duarte-Guterman et

al., 2015, Brinton 2008c, Rapp et al., 2003a).

There are several major pathways through which estrogen may exert neuroprotection; up-

regulation of cholinergic activity in basal forebrain and hippocampus, especially when

neurons are healthy (Gibbs and Aggarwal 1998, Gibbs 2010, Newhouse and Dumas 2015);

increasing the level of neprilysin (an enzyme which degrades amyloid β) (Huang et al.,

2004); acting as an antioxidant in brain; and increasing blood flow and glucose transport in

brain (Brinton 2008b, Rettberg et al., 2014); decreasing tauopathy (Grimm et al., 2016);

decreasing levels of pro-inflammatory cytokines and also by attenuating the stress induced

levels of glucocorticoids (Shivers et al., 2015, Herrera and Mather 2015); it can also activate

prefrontal cortex and medial temporal lobe, thus improving cognition (spatial working

memory, object recognition, and reference memory) (Rapp et al., 2003a, Markowska and

Savonenko 2002).

Estrogen mediated neuroprotection in cognitive tasks involving white matter (such as

reasoning, learning, planning) is selective (Pompili et al., 2012) i.e. estrogen related

neuroprotection is mediated by an increase in levels of brain derived neurotropic factor and

nerve growth factor as well as improving glucose metabolism and cerebral blood flow and

diminishing the amounts of free radicals through its anti-oxidant properties (Monk and

Brodaty 2000).

14

Table 1: Summary of mechanisms of neuroprotection exerted by estrogen and progesterone

Type of estrogen

Mechanism of neuroprotection mediation Reference

Estrogen Through increased functional activity of cholinergic neuronal projections to hippocampus and cerebral cortex

(Gibbs and Aggarwal 1998)

Estradiol Estrogen increases neuronal plasticity in hippocampus through enhanced cholinergic activity in basal forebrain

(Gibbs 2010)

Estradiol Through estradiol-cholinergic interactions (Newhouse and Dumas 2015)

Estradiol Maintaining and increasing the levels of neprilysin in rat brain to normal levels after ovariectomy

(Huang et al., 2004)

Estrogen Estrogen enhances mitochondrial function (aerobic glycolysis) in brain

(Brinton 2008a)

Estrogen Acts as an antioxidant and regulates glucose transport in brain and improves cerebral blood flow

(Rettberg et al., 2014)

Estradiol, progesterone

Both attenuated tauopathy and improved mitochondrial function (increased ATP production) in cellular models of AD

(Grimm et al., 2016)

Estradiol Estrogen has an anti-inflammatory effect (decrease in tumor necrosis factor and interleukin in female rat brain

(Shivers et al., 2015)

Estradiol Estradiol attenuates glucocorticoid mediated damage to cognition

(Herrera and Mather 2015)

Estradiol Estrogen activates multiple areas of brain including prefrontal cortex and medial temporal lobe in ovarectomized rhesus monkeys

(Rapp et al., 2003a)

Estrogen Cyclic provision of estrogen improved working memory among young but not older rats

(Markowska and Savonenko 2002)

Estradiol Estrogen increased spine density in hippocampus of ovarectomized monkeys only when administered cyclically

(Hao et al., 2003)

Estradiol, progesterone

Estradiol and progesterone exerted neuroprotection by decreasing cholinergic deficits, apoptosis and astrogliosis in hippocampus of ovarectomized rat model of AD

(Hu et al., 2016)

Progesterone can confer neuroprotection via several mechanisms including classic genomic

pathways to regulate expression of neurotrophins such as brain derived nerve factor and

non-genomic mechanisms by affecting various signaling pathways (Hu et al., 2016), and by

acting through its own active metabolites i.e. allopregnanolone (Brinton et al. 2008).

Moreover progesterone decreases neural injury, blood brain barrier leakage, and

inflammation in response to ischemia and increases myelination of neurons (de Lignieres

1999).

2.4.3 Sex steroid hormones and aging brain

AD is characterized by an accumulation of amyloid plaques (amyloidopathy) outside the

nerve cells and intracellular tau tangles (tauopathy). Figure 3 depicts the pathway of

metabolism for amyloid precursor protein. Estrogen exerts neuroprotection by increasing

15

APP metabolism through the non-amyloidogenic pathway, thus decreasing the Aβ load and

it also increases Aβ clearance through up-regulating neprilysin and transthyretin levels

(Huang et al., 2004, Barron and Pike 2012, Simpkins et al., 2009).

[Type here]

Amyloid precursor protein (APP)

Metabolized by non-amyloidogenic

pathway (α secretase)

Metabolized by Amyloidogenic

pathway (Protease β secretase)

(BACE))

Larger soluble

β-APPs

Shorter carboxyl

terminals with Aβ

Released from cells and found in

nanomolar levels in soluble state Aβ peptide (40 & 42 AA in length)

No peptides Soluble α APPs

Figure 3: Pathways of Amyloid precursor protein’s metabolism

(Adapted from Barron and Pike. 2012)

Estrogen +

The presence of estrogen receptors in those areas of brain which are affected primarily in AD and dementia led to the hypothesis that loss of neuroprotection at menopause could be a possible mechanism for the higher incidence of AD among women than men (Alzheimer's Association 2016). Aging related high levels of sex hormone-binding globulins and alterations of hypothalamic pituitary gonadal axis result in high peripheral and low brain luteinizing hormone levels which may be linked with the cognitive decline (Blair et al., 2015b, Blair et al., 2015a, Morrison et al., 2006). The menopause related hormonal decline is often associated with central obesity which promotes chronic inflammation and might account for the high incidence of AD among women (Christensen and Pike 2015, Au et al., 2016). After induced or natural menopause, low insulin sensitivity and low leptin levels in conjunction with impaired lipid and glucose metabolism predispose postmenopausal women to a higher risk of inflammation (Boonyaratanakornkit and Pateetin 2015). Certain estrogen receptor polymorphisms (Cheng et al., 2014), a decrease in expression of estrogen receptors (Bean et al., 2014) and decreased synthesis of estrogen and sex hormone-binding globulin as seen in Down’s syndrome (Chace et al., 2012) have all been reported to be associated with an increased risk of AD. Moreover, an increased AD risk was observed among women with estrogen receptor β polymorphism (Zhao et al., 2013, Zhao et al., 2011).

2.4.4 Types of commercially available hormone therapy (HT) and their implications There are various types of commercially available estrogens. Conjugated equine estrogen (CEE) is the most commonly used post-menopausal HT in the United States. The other commonly used estrogen preparation is 17β estradiol which is the most potent form of natural estrogen found in premenopausal women. CEE is composed of estrone sulphate and >10 other compounds (Espeland et al., 2004a). In Finland, women with an intact uterus are administered combination HT which contains estradiol supplemented with norethisterone acetate or levonorgesterel, while women after a hysterectomy use mainly estradiol only (Pentti et al., 2006). Estradiol has a higher binding affinity for both estrogen receptors and

16

also for membrane receptor mediated actions than that of estrone (Harman et al., 2005, Henderson 2006). Orally administered CEE undergoes metabolism in liver and yields various estrone to estradiol ratio ranging from 5:1 to 7:1 in contrast to transdermal estradiol which bypasses liver metabolism and yields an estrone to estradiol in ratio of 1:1 which is similar to that observed in the premenopausal period (Hodis et al., 2001, Wharton et al., 2013). Oral CEE increases the secretion of pro-coagulant proteins and C-reactive protein levels from liver, a property not shared with transdermal estradiol i.e. this latter dosage form does not cause the thromboembolic events associated with CEE and which might underlie some of the unwanted effects encountered in clinical trials (Hogervorst and Bandelow 2009, Lakryc et al., 2015). CEE, but not transdermal estradiol, increases the production of sex hormone- binding globulin, thus estradiol results in higher plasma levels of free estradiol. Moreover, estradiol but not estrone has been associated with improved neuronal survival and activation of hippocampus, thus accounting for the differences in the properties of these different HT formulations (McClure et al., 2013). Naturally occurring progesterone produces an active metabolite called allopregnanolone which has been mainly implicated in progesterone mediated neuroprotection. Medroxyprogesterone acetate (MPA), a synthetic progesterone mostly used in research settings, differs from natural progesterone in multiple ways: MPA does not undergo first pass metabolism unlike naturally occurring progesterone; MPA inhibits the secretion of brain derived nerve factor which is involved in neuroprotection; and MPA exhibits many non-progestagenic effects such as binding to androgen and glucocorticoid receptors unlike natural progesterone. Moreover, MPA also inhibits the beneficial effects of estradiol in cell cultures and prevents the conversion of natural progesterone to its neuroprotective metabolite allopregnanolone. MPA could not increase levels of antiapoptotic B cell lymphoma 2 (Bcl-2) and also inhibited the estrogen mediated increase in Bcl-2. In contrast, natural progesterone has been reported to exert neuroprotection in cerebral cortical and hippocampal neurons through gene regulation and up-regulation of Bcl-2 (Singh and Su 2013). All these mechanisms indicate that naturally occurring progesterone, but not MPA, is neuroprotective. The term phytoestrogens refers to plant derived non-steroidal structural analogs of mammalian estrogens, e.g. resveratrol; these provide a potential alternative to the use of HT; it has been claimed that they exert the same effect as HT but without any significant side effects as observed with regular HT use (Zhao et al., 2013, Soni et al., 2014). Resveratrol has been reported to improve mood and cognition in postmenopausal women through its vasodilating effects and increase in cerebral blood flow (Evans et al., 2016). Oral contraceptives represent another potential marker of lifetime HT use by women during their midlife; which have been associated with the cognition (Warren et al., 2014). Selective estrogen receptor modulators (SERMs) are commercially available therapeutic agents, which are tissue-selective in their estrogen receptor mediated actions (Frick 2012, Walf et al. 2011). Estrogens and antiestrogens act uniformly as agonists and antagonists respectively in target tissues. In contrast, SERMs possess an unusual pharmacology, such that in some tissues (liver, cardiovascular system, bone) they act as agonists, whereas they function as antagonists in other tissues (brain and breast tissue). The therapeutic potential of SERMs is promising, perhaps they can confer the beneficial effects of estrogen in bone (osteoporosis) and heart, while at the same time preventing the peripheral harmful effects associated with estrogens such as breast and endometrial cancer by acting as estrogen antagonists in these tissues (Riggs and Hartmann 2003, Lewis and Jordan 2005). An association of HT use with a higher risk of cardiovascular disease, thromboembolic events, gall bladder disease, dementia, and breast cancer has been observed in the past (Hulley et

17

al., 2002, Majoribanks et al., 2012, Boardman et al., 2015); this may be reduced by treatment with SERMs which can mimick estrogen’s agonistic properties in brain while preventing systemic estrogen related harmful effects such as breast and endometrial cancer etc. Currently available SERMs, such as tamoxifen and raloxifene, both of which are used as chemopreventive agents in estrogen receptor positive breast cancer as well as prophylaxis to prevent fractures among postmenopausal women (Lewis and Jordan 2005). However, both raloxifene and tamoxifene have not shown promising effects on cognition among older women >65 years (Espeland et al. 2010).

2.5 MENOPAUSE

Menopause is a physiological state in a woman’s life characterized by cessation of menstrual cycles and is marked by senescence of ovarian hormones (estrogens and progesterone). The average age at menopause is 51 years and is considered a midlife event due to marked increase in life span compared to previous century (Rocca et al. 2009, Armstrong et al. 2004).

2.5.1 Types and stages of menopause Menopause occurs either naturally among most females or can be induced at any age after menarche and before the onset of natural menopause. There are several reasons of induced menopause: removal of ovaries, or uterus and ovaries due to benign or malignant conditions; premature ovarian insufficiency; or chemotherapy or radiotherapy in pelvic area (Shuster et al., 2010, Podfigurna-Stopa et al., 2016). Induced menopause is categorized as early menopause or premature menopause if it occurs between 40-45 years of age or <40 years respectively. Natural menopause results in a gradual depletion of sex hormones over a period of certain years whereas induced menopause results in an abrupt cessation of hormone synthesis. Climacteric symptoms characterize the imminent menopause e.g. vasomotor symptoms caused by disturbances in hypothalamic thermoregulation due to estrogen depletion; sleep disturbances, mood disorders, anxiety, hot flashes, fatigue, and depression (Roberts and Hickey 2016). Currently, HT is the only effective pharmacotherapy available to ease the vasomotor symptoms (Abdi et al., 2016). There are some alternative therapies (herbals, ginseng, acupuncture, yoga etc) to treat vasomotor symptoms, but these are not as effective as HT (Kim et al., 2015). The severity of experiencing menopausal symptoms differs between women, depending upon many sociodemographic, psychological, and lifestyle related factors, such as education, socioeconomic status, occupation, smoking, relationship status, physical activity, history of oophorectomy, stress, and body mass index (Makara-Studzinska et al., 2015). Menopause has been categorized into following phases based on guidelines devised at a workshop on reproductive aging: perimenopause, menopausal transition, menopause, and post-menopause (Soules et al., 2001, Harlow et al., 2012). Perimenopause is an important stage where a woman’s midlife health status is determining her future health (ESHRE Capri Workshop Group 2011). The treatment of menopausal symptoms requires both a timely evaluation and a diagnosis of stage of menopause along with the exclusion of other differential diagnoses. The National Collaboration Center for Women’s and Children’s Health recommends an individual approach in the management of all stages of menopause. The woman’s own choice should be considered after informing her about potential harms of HT and any previous and current use of HT should be inquired. HT can be offered as estrogen alone in women without a uterus and combined with progesterone in those with

18

an intact uterus for short period of time to relieve vasomotor symptoms and also to improve quality of life and the overall health status (Rockville 2015).

2.5.2 Short term and long term implications of menopause Menopause exposes women to a compromised state of health due to the depletion of previously available sex steroid hormones. Induced menopause, or more specifically premature menopause, increases the risk of heart and neurological diseases (Podfigurna-Stopa et al., 2016). It can be due to elevated sensitivity of the brain to the hormonal loss and the related stress; it can be avoided by provision of HT immediately after induced menopause until the age of natural menopause (Scott et al., 2014). Bilateral oophorectomy was associated with an increased risk of all-cause mortality in the Nurses’ Health Study and similarly decreased endogenous estrogen levels were related to high serum lipid levels and a higher risk of atherosclerosis (Parker et al., 2009). It has been argued that the menopause related decline in the production of sex steroid hormones increases the risk of oxidative stress which may be a factor triggering the higher incidence of dementia among women as they age, and thus it can be attenuated by provision of estrogens (Cervellati and Bergamini 2016). The presence of estrogen and progesterone receptors in blood vessels and heart forms the foundation for the potential role of these hormones in cardiovascular health through vasodilatation and nitric oxide production, decreasing atherosclerosis, vascular injury and smooth muscle cell growth while promoting endothelial cell growth (Mendelsohn and Karas 1999). The depletion of sex steroid hormones after menopause might account for the higher incidence of heart disease among females (Mendelsohn and Karas 2005). Since the association of vascular and metabolic disorders with AD is plausible, one could argue that they might share a common mechanism (Craft 2009). In the Women’s Health Initiative-Coronary Artery Calcium study, estrogen therapy reduced coronary artery calcification among younger menopausal women (average age 55) but not in older women. This differential effect may be due to the differences occurring in the expression of estrogen receptors and gene expression in calcium homeostasis as the woman ages (Mendelsohn and Karas 2007).

2.6 HORMONE THERAPY AND RISK OF AD, DEMENTIA AND COGNITIVE DECLINE IN WOMEN

The association between HT use with respect to menopause and its implications on cognition, AD and dementia are a complex scenario; it is modulated by a plethora of midlife, lifestyle, demographic, and genetic factors affecting either the use of HT or its impact on neuroprotection (Goveas et al., 2016). Basic experimental studies have provided evidence that estrogen is neuroprotective and this association has been confirmed in observational studies, but clinical trials have mainly failed to detect any neuroprotective effect of estrogens in postmenopausal women. There may be several reasons to account for the discrepant findings between basic experimental and human studies: 1. Protective effect of HT on cognitive decline and dementia can be observed if HT is started early after menopause - this theory is called the critical window theory/hypothesis (Sherwin and Henry 2008, Sherwin 2006, Sherwin 2012, Maki 2013b); 2. Brain neurons respond better to HT when they are healthy around menopause, not 10-20 years post-menopause, when they might have already undergone degeneration thus rendering HT detrimental at this stage - this can be termed as “healthy cell theory/bias” (Henderson 2006, Maki 2013a). The estrogen receptor α has been found to

19

become sequestered in the tau-tangles which might partly explain the lack of neuroprotection with use of HT in old age when AD pathology is established (Wang et al., 2016). If neurons are treated when they are healthy, it can be beneficial, otherwise it is not (Siegfried 2007); 3. Differences in formulations, and dose of HT between observational and clinical trials (Sherwin 2007, Hogervorst and Bandelow 2007, Fischer et al., 2014) where positive associations have been observed with use of 17β estradiol in observational studies rather than CEE, which has been the most commonly used formulation in randomized controlled trials (RCT) (Sherwin 1988, Duka et al., 2000, Phillips and Sherwin 1992); 4. Route of HT administration may also be important with respect to the HT-cognition association (Hogervorst and Bandelow 2009). This can be due to the fact that orally delivered CEE undergoes first pass metabolism in liver, thus decreasing its bioavailability in contrast to transdermal estradiol, which bypasses hepatic first pass metabolism (Ansbacher 2001). Moreover, transdermal and intramuscular estradiol cross the blood brain barrier more effectively than the main metabolite of CEE (estrone sulphate) (Steingold et al., 1986); 5. The healthy user bias theory which implies that women using HT are generally more healthy, better educated, have a higher socioeconomic status, and are consequently less prone to develop dementia either due to high cognitive and brain reserve or their better overall health status (Henderson and Sherwin 2007, Maki 2013a). APOE Ɛ4 status is an important determinant of AD-HT relationship among females, which is associated in a complex, and still poorly defined manner with estrogens to increase risk of AD among women homozygous or heterozygous for this allele (Rebeck and Manaye 2013, Riedel et al., 2016). APOE ε4 increases the production of Aβ, decreases vertebral bone density (Rodriguez et al., 2013), and furthermore some of its detrimental effects are not mediated through the amyloid pathway (Rodriguez et al., 2013).

2.6.1 Clinical trials Table 2 describes clinical trials conducted among postmenopausal women in various populations over diverse time frames. The largest clinical trial to date examining the association between HT and dementia is Women’s Health Initiative Memory Study (WHIMS), which included women >65 years of age and it was intended to estimate the risk of global dementia as a secondary outcome. The overall use of postmenopausal HT increased the dementia risk and the trial was terminated before completion. In WHIMS, the use of CEE+MPA based HT was associated with an increased risk of dementia and cognitive decline (Rapp et al., 2003b, Shumaker et al., 2004a, Shumaker et al., 2003a, Resnick et al., 2006). In more detail, the use of CEE alone was associated with the following outcomes: adverse cognition among those women who had low cognitive function at baseline (Espeland et al., 2004b); no significant increase in probable dementia (Espeland et al., 2004c); and no significant effect on verbal memory (Resnick et al., 2009, Espeland et al., 2013a). Similarly, no protective association of postmenopausal HT with cognition or dementia has been detected in some other trials (Yaffe et al., 2006, Gleason et al., 2015, Grady et al., 2002, Maki et al., 2007, Almeida et al., 2006), although beneficial effects of HT on selective cognitive domains either directly or through relief of VMS have been observed in a few trials (Sherwin and Grigorova 2011, Marinho et al., 2008, Alhola et al., 2010, Joffe et al., 2006, Asthana et al., 2001, Shaywitz et al., 2003, Wharton et al., 2011, Berent-Spillson et al., 2015, Kocoska-Maras et al., 2011, Baker et al., 2012, Albertazzi et al., 2000). The negative findings emerging from the WHIMS trial can be explained by considering certain limitations; women in the WHIMS trial were rather old (65-79 years) with mean age of 72; either oral CEE+MPA or CEE regimen were used; the women in the trial had a high rate of co-morbidities at baseline, 55% were hypertensive, 11% diabetic, and 23% were

20

morbidly obese; and women showing structural brain changes in these trials had low Modified Mini Mental Scale (3MS) examination scores at baseline (Sherwin 2007, Coker et al., 2010). The individual’s age, reproductive age or both are important determinants in the critical window theory (Maki 2013b) and health and cognitive status at baseline are important predictors of how HT can influence cognition. Women with age-independent low cognitive status at baseline perform worse after HT use than those women with high cognitive scores at baseline. This effect was observed in WHIMS where HT related loss of brain volume was higher among those women with low 3MS scores at baseline (Maki 2013b). These findings mean that there are serious limitations to generalizing the WHIMS findings to young peri-menopausal women, early surgically menopausal women, and those using different types, doses and routes of HT and who are healthy at baseline. Moreover, the findings from WHIMS among young women that there were no significant detrimental effects with short and long term HT use as well as in the Kronos Early Estrogen Prevention Study-cognitive and affective (KEEPS-cog) trials should reassure younger women who have recently become menopausal that HT, especially if administered for a shorter duration of time, if not actually preventing, should not increase their risk of developing AD (Cesaroni and Rossi 2015).

21

Tab

le 2

: Ran

do

miz

ed c

on

tro

lled

tri

als

exa

min

ing

the

effe

ct o

f p

ost

men

op

ausa

l HT

on

ris

k o

f co

gnit

ive

dec

line,

dem

eti

a, a

nd

AD

Stu

dy,

Co

un

try,

Fo

llow

-up

tim

e P

arti

cip

ant’

s ch

arac

teri

stic

s In

terv

enti

on

(H

T ty

pe

and

do

sage

) O

utc

om

e M

ain

re

sult

s

WH

IMS

(ran

do

miz

ed, d

ou

ble

blin

d, p

lace

bo

co

ntr

olle

d c

linic

al t

rial

), U

SA

Rap

p e

t al

.,

200

3

4.2

yea

rs

438

1

≥65

yea

rs

wit

h in

tact

ute

rus

1 d

aily

tab

let

of

0.6

25 m

g C

EE

+ 2

.5 m

g o

f M

PA

G

lob

al c

ogn

itiv

e fu

nct

ion

(M

MSE

) O

vera

ll n

o c

linic

ally

sig

nif

ican

t ef

fect

o

n c

ogn

itio

n o

bse

rve

d in

inte

rven

tio

n

gro

up

co

mp

ared

to

pla

ceb

o.

Shu

mak

er e

t al

. 2

003

4

.05

yea

rs

453

2

≥65

yea

rs

Wit

h in

tact

ute

rus

1 d

aily

tab

let

of

0.6

25 m

g C

EE

+ 2

.5m

g M

PA

In

cid

ence

of

pro

bab

le d

emen

tia

(pri

mar

y o

utc

om

e) a

nd

MC

I (s

eco

nd

ary

ou

tco

me)

CEE

+MP

A u

se in

crea

sed

th

e co

mb

ined

ri

sk o

f p

rob

able

dem

enti

a an

d M

CI

com

par

ed t

o p

lace

bo

.

Esp

elan

d e

t al

.,

200

4

5.4

yea

rs

280

8

65

-79

yea

rs

pri

or

hys

tere

cto

my

1 d

aily

tab

let

of

0.6

25 m

g C

EE

Glo

bal

co

gnit

ive

fun

ctio

n (

MM

SE)

C

EE u

se h

ad a

n a

dve

rse

eff

ect

on

co

gnit

ion

esp

ecia

lly a

mo

ng

tho

se

wo

me

n w

ith

low

er c

ogn

itiv

e fu

nct

ion

at

bas

elin

e.

Shu

mak

er e

t al

., 2

004

7

-9 y

ears

747

9

65

-79

yea

r W

ith

an

d w

ith

ou

t h

yste

rect

om

y

E al

on

e tr

ial:

1 d

aily

tab

let

of

0.6

25

mg

CEE

E+

P t

rial

: 1 d

aily

tab

let

of

0.6

25

mg

CEE

+ 2

.5 m

g M

PA

Pro

bab

le d

emen

tia

and

MC

I In

co

mb

ined

an

alys

is o

f es

tro

gen

al

on

e an

d e

stro

gen

+ p

roge

stin

tri

als,

in

crea

sed

ris

k o

f d

emen

tia

and

MC

I w

as o

bse

rved

co

mp

ared

to

pla

ceb

o.

Res

nic

k et

al.

200

6

1.3

5 y

ears

141

6

≥65

yea

rs

Inta

ct u

teru

s

1 d

aily

tab

let

of

0.6

25 m

g C

EE

+ 2

.5 m

g M

PA

C

ogn

itiv

e fu

nct

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s (a

tten

tio

n,

wo

rkin

g m

emo

ry, f

igu

ral m

emo

ry,

fin

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oto

r sp

eed

, ver

bal

flu

ency

) an

d a

ffec

t

Inte

rven

tio

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rou

p d

isp

laye

d a

dec

line

in v

erb

al m

emo

ry, a

po

siti

ve t

ren

d o

n

figu

ral m

emo

ry, a

nd

no

sig

nif

ican

t e

ffec

t o

n a

ffec

t co

mp

ared

to

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ceb

o.

Res

nic

k et

al.,

2

009

2

.7 y

ears

886

≥

65 y

ears

p

rio

r h

yste

rect

om

y

1 d

aily

tab

let

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25 m

g C

EE

Rat

e o

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ange

in c

ogn

itiv

e fu

nct

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s an

d a

ffec

t N

o s

ign

ific

ant

effe

ct o

f C

EE b

ased

HT

was

ob

serv

ed o

n c

ogn

itiv

e d

om

ain

s an

d a

ffec

t co

mp

ared

to

pla

ceb

o.

Esp

elan

d e

t al

. 2

013

7

.2 y

ears

132

6

50

-55

yea

rs

Wit

h a

nd

wit

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ut

hys

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cto

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aily

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let

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25 m

g C

EE

wit

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r w

ith

ou

t 2

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g M

PA

G

lob

al c

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e fu

nct

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an

d

vari

ou

s co

gnit

ive

do

mai

ns

(ver

bal

m

emo

ry, a

tten

tio

n, e

xecu

tive

fu

nct

ion

, ver

bal

flu

ency

, wo

rkin

g m

emo

ry)

No

ove

rall

ben

efic

ial o

r h

arm

ful e

ffec

t o

n g

lob

al c

ogn

itiv

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nct

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or

cogn

itiv

e d

om

ain

s w

as s

een

wit

h C

EE

bas

ed t

her

apy

com

par

ed t

o p

lace

bo

.

22

Oth

er t

rial

s

Alb

erta

zzi e

t al

. 2

000

, Ita

ly

Sin

gle

-blin

d R

CT

6 m

on

ths

22

(1

4

com

ple

ted

) 5

1-5

7 y

ears

old

Tib

olo

ne

vers

us

com

bin

atio

n o

f n

ore

this

tero

ne

acet

ate

1m

g +

es

trad

iol v

aler

ate

2m

g

Mem

ory

(re

cogn

itio

n a

nd

se

man

tic

mem

ory

), m

oo

d a

nd

lib

ido

Estr

adio

l an

d n

ore

this

tero

ne

com

bin

atio

n w

as s

ligh

tly

mo

re

effe

ctiv

e th

an t

ibo

lon

e in

imp

rovi

ng

cogn

itio

n.

Ast

han

a e

t al

. 2

001

, USA

D

ou

ble

-blin

d R

CT

8 w

eeks

20

w

ith

mild

-m

od

erat

e A

D

61

-90

yea

rs o

ld

Skin

pat

ch o

f 0

.10

mg

17

β

estr

adio

l per

day

ver

sus

pla

ceb

o

Neu

rop

sych

olo

gica

l tes

ts f

or

atte

nti

on

, ver

bal

, vis

ual

, an

d

sem

anti

c m

emo

ry

Estr

oge

n t

her

apy

sign

ific

antl

y im

pro

ved

att

enti

on

, vis

ual

an

d v

erb

al

mem

ory

, an

d s

eman

tic

mem

ory

co

mp

ared

to

pla

ceb

o.

Gra

dd

y e

t al

. 2

002

, USA

R

CT

4.2

yea

rs

106

3

<80

year

s w

ith

hea

rt

dis

ease

an

d in

tact

u

teru

s

1 d

aily

tab

let

of

0.6

25 m

g C

EE +

2

.5 m

g M

PA

(2

.5m

g) v

ersu

s p

lace

bo

Co

gnit

ive

fun

ctio

ns

usi

ng

3M

S,

Ver

bal

Flu

ency

, Bo

sto

n N

amin

g,

Wo

rd L

ist

Mem

ory

, Wo

rd L

ist

Rec

all,

and

Tra

ils B

te

sts

No

sig

nif

ican

t ef

fect

of

HT

ob

serv

ed

on

co

gnit

ive

sco

res

exc

ept

for

a d

eclin

e in

ver

bal

flu

ency

tes

t co

mp

ared

to

pla

ceb

o g

rou

p.

Shay

wit

z et

al.

200

3, U

SA

Do

ub

le-b

lind

RC

T 2

1 d

ays

60

M

ean

age

= 5

1.2

ye

ars

1 d

aily

tab

let

of

1.2

5 m

g C

EE

vers

us

pla

ceb

o

Ora

l rea

din

g (G

rey

ora

l rea

din

g te

st)

and

tes

ts f

or

verb

al

mem

ory

CEE

use

rs p

erfo

rmed

bet

ter

in o

ral

read

ing

and

ver

bal

mem

ory

tes

ts

com

par

ed t

o p

lace

bo

.

Yaff

e et

al.

200

6, U

SA

Do

ub

le-b

lind

R

CT

2 y

ears

417

6

0-8

0 y

rs

wit

h in

tact

ute

rus

Wee

kly

tran

sder

mal

pat

ch

del

iver

ing

0.0

14

mg

estr

adio

l per

d

ay v

ersu

s p

lace

bo

Co

gnit

ive

fun

ctio

ns

(lan

guag

e,

visu

osp

atia

l mem

ory

, exe

cuti

ve

fun

ctio

n, s

eman

tic

mem

ory

),

HR

QO

L b

y SF

-36

No

sta

tist

ical

ly s

ign

ific

ant

dif

fere

nce

in

cogn

itiv

e te

st s

core

s o

r H

RQ

OL

was

o

bse

rved

in e

stra

dio

l co

mp

ared

to

p

lace

bo

gro

up

.

Alm

eid

a et

al.

200

6

Do

ub

le-b

lind

RC

T 2

0 w

eeks

115

≥

70 y

ears

old

Es

trad

iol

2m

g p

er d

ay

vers

us

pla

ceb

o

Mo

od

, qu

alit

y o

f lif

e, v

ario

us

cogn

itiv

e fu

nct

ion

s (e

.g. v

erb

al

flu

ency

, mem

ory

, lea

rnin

g)

No

sig

nif

ican

t im

pro

vem

ent

in

cogn

itio

n, m

oo

d a

nd

qu

alit

y o

f lif

e w

as

ob

serv

ed w

ith

est

rad

iol c

om

par

ed t

o

pla

ceb

o g

rou

p.

Joff

e, e

t al

. 2

006

, USA

D

ou

ble

-blin

d R

CT

12

wee

ks

52

4

0-6

0 y

ears

p

eri

and

ear

ly

po

stm

eno

pau

sal

Tran

sder

mal

est

rad

iol 0

.05

m

g/d

ay p

atch

ver

sus

pla

ceb

o

Var

iou

s co

gnit

ive

fun

ctio

ns

(e.g

. ve

rbal

rec

all,

spat

ial m

emo

ry,

exec

uti

ve f

un

ctio

ns)

, fu

nct

ion

al

MR

I du

rin

g co

gnit

ive

task

s

Estr

adio

l im

pro

ved

ver

bal

rec

all a

nd

sh

ow

ed s

ign

ific

antl

y h

igh

er a

ctiv

atio

n

of

pre

fro

nta

l co

rte

x d

uri

ng

verb

al a

nd

w

ork

ing

mem

ory

tas

ks c

om

par

ed t

o

pla

ceb

o.

23

Mak

i et

al.

200

7, U

SA

Do

ub

le-b

lind

RC

T 4

mo

nth

s

180

4

5-5

5 y

ears

1

dai

ly t

able

t o

f 0

.625

mg

CEE

+

2.5

mg

MP

A v

ersu

s p

lace

bo

M

emo

ry, a

tten

tio

n, s

ub

ject

ive

co

gnit

ion

, aff

ect,

sle

ep

qu

alit

y,

qu

alit

y o

f lif

e

Neg

ativ

e e

ffec

t o

f H

T u

se o

n s

ho

rt a

nd

lo

ng

term

ver

bal

mem

ory

wh

ile

imp

rove

men

t in

VM

S an

d g

ener

al

qu

alit

y o

f lif

e o

bse

rved

co

mp

ared

to

p

lace

bo

.

Mar

inh

o e

t al

. 2

008

, Bra

zil

Clin

ical

tri

al

12

wee

ks

74

4

8-6

5 y

ears

1

dai

ly t

able

t o

f 2m

g 1

7 b

eta-

estr

adio

l ver

sus

pla

ceb

o

MM

SE, a

tten

tio

n, l

angu

age,

sh

ort

-ter

m m

emo

ry, g

lob

al

cogn

itiv

e fu

nct

ion

, vis

ual

sea

rch

Estr

oge

n im

pro

ved

vas

om

oto

r sy

mp

tom

s b

ut

no

ben

efic

ial e

ffec

t o

n

cogn

itio

n w

as o

bse

rved

co

mp

ared

to

p

lace

bo

.

Alh

ola

et

al.

201

0, F

inla

nd

D

ou

ble

-blin

d

clin

ical

tri

al

6 m

on

ths

Gro

up

1: 1

6

pre

men

op

ausa

l 4

5-5

1 y

ears

G

rou

p 2

: 16

p

ost

men

op

ausa

l 5

8-7

0 y

rs

Gro

up

1: C

yclic

2m

g e

stra

dio

l an

d

1m

g n

ore

this

tero

ne

acet

ate

vers

us

pla

ceb

o

Gro

up

2: C

on

tin

uo

us

2m

g es

trad

iol v

aler

ate+

0.7

mg

no

reth

iste

ron

e ac

etat

e ve

rsu

s p

lace

bo

Var

iou

s co

gnit

ive

fun

ctio

ns

(e.g

. ve

rbal

an

d v

isu

om

oto

r fu

nct

ion

, ve

rbal

mem

ory

, co

gnit

ive

atte

nti

on

, vis

ual

mem

ory

)

Gro

up

1: H

T u

se im

pro

ved

co

gnit

ive

atte

nti

on

bu

t p

lace

bo

sh

ow

ed

bet

ter

per

form

ance

in s

har

ed a

tten

tio

n a

nd

au

dit

ory

att

enti

on

te

sts.

G

rou

p 2

: HT

imp

rove

d v

erb

al e

pis

od

ic

mem

ory

co

mp

ared

to

pla

ceb

o.

Sher

win

an

d

Gri

goro

va

201

1, C

anad

a D

ou

ble

-blin

d

RC

T 1

2 w

eeks

24

5

0-5

5 y

ears

w

ith

inta

ct u

teru

s

Wo

men

ass

ign

ed t

o o

ne

of

follo

win

g gr

ou

ps

1. C

EE+p

lace

bo

OR

2

. CEE

+MP

A O

R

3. C

EE+m

icro

niz

ed p

roge

ster

on

e

Mo

od

, ver

bal

mem

ory

, vi

suo

spat

ial s

equ

enci

ng,

w

ork

ing

mem

ory

CEE

+mic

ron

ized

pro

gest

ero

ne

gro

up

h

ad b

ette

r w

ork

ing

mem

ory

sco

re

than

oth

er 2

gro

up

s.

No

ch

ange

s in

co

gnit

ive

sco

res

ob

serv

ed in

CEE

+MP

A o

r C

EE+

pla

ceb

o

gro

up

s.

Mo

od

imp

rove

d in

all

gro

up

s.

Wh

arto

n e

t al

. 2

011

, USA

D

ou

ble

-blin

d R

CT

3 m

on

ths

43

M

ean

age

74

ye

ars

Wit

h m

ild-

mo

der

ate

AD

Low

an

d h

igh

do

ses

of

17

β

estr

adio

l p

atch

+ p

lace

bo

or

MP

A

tab

let

vers

us

pla

ceb

o p

atch

an

d

pla

ceb

o t

able

t

Sem

anti

c m

emo

ry, v

isu

al

mem

ory

, ver

bal

flu

ency

, ver

bal

m

emo

ry, c

om

ple

x fi

gure

tes

t,

atte

nti

on

Estr

adio

l + M

PA

gro

up

imp

rove

d v

isu

al

mem

ory

co

mp

ared

to

est

rad

iol a

lon

e gr

ou

p.

HT

use

gro

up

s sh

ow

ed

bet

ter

visu

al

and

se

man

tic

mem

ory

co

mp

ared

to

p

lace

bo

gro

up

.

Bak

er e

t al

. 2

012

R

CT

8 w

eeks

39

5

6-8

4 y

ears

Tr

ansd

erm

al e

stra

dio

l 0.1

0 m

g/d

L ve

rsu

s p

lace

bo

+ 9

0 m

g/d

of

ora

l h

ydro

cort

iso

ne

in la

st 4

day

s in

b

oth

gro

up

s

Ver

bal

mem

ory

, sel

ecti

ve

atte

nti

on

, wo

rkin

g m

emo

ry,

wo

rd f

luen

cy, s

tre

ss

Estr

adio

l alo

ne

imp

rove

d v

erb

al a

nd

w

ork

ing

mem

ory

co

mp

ared

to

p

lace

bo

. C

ort

iso

l ad

min

istr

atio

n d

imin

ish

ed

po

siti

ve c

ogn

itiv

e ef

fect

s o

f es

trad

iol.

24

Ber

net

-Sp

illso

n e

t al

. 20

15

, USA

C

ross

-ove

r R

CT

90

day

s

29

4

5-5

5 y

ears

O

ral e

stra

dio

l O

ral p

roge

ste

ron

e

cou

nte

rbal

ance

d w

ith

pla

ceb

o

Fun

ctio

nal

MR

I, s

eru

m h

orm

on

e le

vels

, ver

bal

an

d v

isu

al m

emo

ry

HT

use

incr

ease

d p

refr

on

tal c

ort

ex

acti

vati

on

du

rin

g co

gnit

ive

task

s an

d

may

hav

e p

ote

nti

al t

o im

pro

ve

cogn

itio

n

Gle

aso

n e

t al

. 2

015

, USA

D

ou

ble

-blin

d R

CT

Mea

n le

ngt

h o

f fo

llow

-up

2.8

5

year

s

693

M

ean

age

52

.6

year

s

Gro

up

1: O

ral C

EE (

0.4

5 m

g/d

ay)

+ m

icro

niz

ed p

roge

ste

ron

e (2

00

m

g/d

ay)

Gro

up

2: T

ran

sder

mal

est

rad

iol

(50

µ/d

ay)

+ m

icro

niz

ed

pro

gest

ero

ne

(20

0 m

g/d

ay)

Gro

up

3: P

lace

bo

3M

S an

d t

est

s fo

r va

rio

us

cogn

itiv

e fu

nct

ion

s (v

erb

al a

nd

le

arn

ing

mem

ory

, wo

rkin

g m

emo

ry, e

xecu

tive

fu

nct

ion

, la

ngu

age

M

oo

d

HT

had

nei

ther

ben

efic

ial n

or

har

mfu

l ef

fect

s o

n c

ogn

itiv

e sc

ore

s.

Ora

l CEE

use

bu

t n

ot

tran

sder

mal

es

trad

iol i

mp

rove

d s

ymp

tom

s o

f an

xiet

y an

d d

epre

ssio

n.

Hen

der

son

et

al.

201

6, U

SA

Do

ub

le-b

lind

RC

T 5

yea

rs

567

Ea

rly

po

stm

eno

pau

sal

gro

up

: mea

n a

ge

55

.6 y

ears

La

te

po

stm

eno

pau

sal

gro

up

: mea

n a

ge

65

yea

rs

1 d

aily

tab

let

of

1 m

g 1

7β

estr

adio

l ver

sus

pla

ceb

o

Wit

h in

tact

ute

rus:

1 m

g 1

7β

estr

adio

l + c

yclic

mic

ron

ized

p

roge

ster

on

e ge

l (45

mg)

ver

sus

pla

ceb

o

Ver

bal

ep

iso

dic

mem

ory

, e

xecu

tive

fu

nct

ion

s, g

lob

al

cogn

itio

n

HT

was

nei

ther

ben

efic

ial n

or

har

mfu

l fo

r co

gnit

ion

in b

oth

ear

ly a

nd

late

p

ost

men

op

ausa

l gro

up

s co

mp

ared

to

p

lace

bo

Ab

bre

viat

ion

s: A

D:

Alz

hei

mer

’s d

isea

se;

CEE

: co

nju

gate

d e

qu

ine

estr

oge

ns;

MP

A: m

edro

xyp

roge

ste

ron

e ac

etat

e; M

MSE

: Min

i Men

tal

Scal

e Ex

amin

atio

n;

HT:

ho

rmo

ne

ther

apy;

MC

I: m

ild c

ogn

itiv

e im

pai

rmen

t; 3

MS:

mo

dif

ied

min

i men

tal s

cale

exa

min

atio

n;

VM

S: v

aso

mo

tor

sym

pto

ms;

RC

T: r

and

om

ized

co

ntr

olle

d

tria

ls;

USA

: U

nit

ed S

tate

s o

f A

mer

ica;

WH

IMS:

Wo

men

’s H

ealt

h I

nit

iati

ve M

emo

ry S

tud

y; V

MS,

vas

om

oto

r sy

mp

tom

s; H

RQ

OL,

Hea

lth

-rel

ated

qu

alit

y o

f lif

e;

MR

I: m

agn

etic

res

on

ance

imag

ing.

25

2.6.2 Observational studies Observational studies are aimed to explore the exposure-outcome relationship over a long period of time while providing information on multiple co-variables and confounders pertinent to the specific outcome and exposure. Table 3 summarizes the main findings from observational studies between HT use and the risk of cognitive decline and dementia. Studies exploring the use of HT with AD have made the following conclusions: long-term postmenopausal HT use for ≥10 years decreased risk of AD if started early in menopause (Shao et al., 2012, Bove et al., 2014, Zandi et al., 2002b); high life-time exposure to endogenous estrogens protected against AD [Fox et al., 2013]; although one case-control study did not observe a protective association between HT and AD (Roberts et al., 2006), in other case-control studies, HT use has been associated with a lower risk of AD in the youngest age group (50-63 years) (Henderson et al., 2005), an effect that was independent of education and age at menopause (Waring et al., 1999). Studies with other measures of HT use and with cognitive decline and dementia as the main outcome yielded the following results: 1. Increased lifetime exposure to endogenous estrogens improved cognitive functions (Hesson 2012, Rasgon et al. 2005); 2. Lifetime use of HT decreased cognitive decline (Carlson et al., 2001); 3. Current use of HT improved cognition (Steffens et al., 1999) and past and current HT users had better cognitive functions than non-users (Ghidoni et al., 2006); 4. Early use near menopause was more protective against cognitive decline than late use (Whitmer et al., 2011, Greendale et al., 2009, Galen Buckwalter et al., 2004, MacLennan et al., 2006); 5. HT users had better verbal memory, abstract reasoning, and visuospatial skills than non-users (Maki et al., 2011, Wharton et al., 2009a, Duff and Hampson 2000, Maki et al., 2001); 6. High serum estradiol levels at baseline were protective against cognitive decline and vice versa (Yaffe et al., 2000b, Yaffe et al., 2006); 7. The use of 17-β estradiol was more effective than CEE at improving verbal memory (Wroolie et al., 2011); 8. In a few studies, the use of HT was not protective against cognitive decline and dementia (Petitti et al., 2008, Kang et al., 2004a); 9. The protective effect of HT on cognition depends upon APOE ε4 status. In one study, the use of HT among APOE Ɛ4 negative women was protective against cognitive decline but not among APOE Ɛ4 carrier women (Yaffe et al. 2000a). In contrast, in another study, among current HT users, the risk of dementia was not increased significantly in the APOE Ɛ4 carrier women (Ryan et al. 2009). The difference in results between observational and clinical studies may be attributable to differences in sample selection, duration of follow-up, dropout rate, type, duration, and formulation of HT, and time of initiation as well as the women’s baseline health statuses (Monk and Brodaty 2000).

26

Tab

le 3

: Ob

serv

atio

nal

stu

die

s e

xam

inin

g th

e as

soci

atio

n b

etw

een

po

stm

eno

pau

sal H

T an

d r

isk

of

cogn

itiv

e d

eclin

e, d

eme

nti

a, a

nd

AD

Stu

dy,

C

ou

ntr

y,

follo

w-u

p

tim

e

Sam

ple

fe

atu

res

Info

rmat

ion

on

h

orm

on

e th

erap

y

Ou

tco

me

Co

vari

ates

M

ain

re

sult

s

CO

HO

RT

STU

DIE

S

Stef

fen

s et

al.

199

9, U

SA

2 y

ears

233

8

≥ 6

5 y

ears

Se

lf-r

epo

rted

es

tro

gen

use

G

lob

al c

ogn

itio

n (

3MS)

in

a s

tru

ctu

red

in

terv

iew

AP

OE

stat

us,

dem

ogr

aph

ics,

m

edic

al a

nd

gyn

eco

logi

cal h

isto

ry,

lifes

tyle

fac

tors

Cu

rren

t es

tro

gen

use

was

as

soci

ate

d w

ith

hig

h 3

MS

sco

re

ind

epen

den

tly.

Yaff

e et

al.

200

0, U

SA

6 y

ears

425

≥

65

yea

rs

Seru

m

con

cen

trat

ion

o

f e

stra

dio

l an

d

test

ost

ero

ne

at

bas

elin

e

Co

gnit

ion

ass

esse

d a

t b

asel

ine

and

aft

er 6

ye

ars

usi

ng

mo

dif

ied

ve

rsio

n o

f M

MSE

Dem

ogr

aph

ic f

acto

rs, m

edic

al

his

tory

, gyn

eco

logi

cal h

isto

ry,

lifes

tyle

fac

tors

Hig

h c

on

cen

trat

ion

of

bio

avai

lab

le

estr

adio

l (en

do

gen

ou

s e

stro

gen

) w

as a

sso

ciat

ed

wit

h le

ss li

kelih

oo

d

of

dev

elo

pin

g co

gnit

ive

imp

airm

ent.

Yaff

e K

2

000

, USA

6

yea

rs

271

6

≥ 6

5 y

ears

Se

lf-r

epo

rted

cu

rren

t an

d p

ast

use

of

ora

l es

tro

gen

s an

d

pro

gest

ero

ne

An

nu

al c

ogn

itiv

e as

sess

men

t (3

MS)

Dem

ogr

aph

ic a

nd

life

styl

e fa

cto

rs,

inte

rnal

car

oti

d w

all t

hic

knes

s,

AP

OE

stat

us

AP

OE

no

n-c

arri

er w

om

en u

sin

g es

tro

gen

th

erap

y cu

rren

tly

had

less

co

gnit

ive

dec

line

. Es

tro

gen

use

was

ass

oci

ated

wit

h

less

car

oti

d w

all t

hic

ken

ing.

Car

lso

n e

t al

. 2

001

, USA

5

yea

rs

207

3

≥6

5 y

ears

Ev

er v

s. n

ever

, p

ast

and

p

rese

nt

use

of

HT

Glo

bal

co

gnit

ion

(M

MSE

) A

PO

E st

atu

s, d

emo

grap

hic

s,

occ

up

atio

n h

isto

ry, p

sych

iatr

ic a

nd

m

edic

al h

isto

ry, e

du

cati

on

, cal

ciu

m

and

mu

ltiv

itam

ins

inta

ke

Life

tim

e H

T u

se im

pro

ved

glo

bal

co

gnit

ion

an

d d

ecre

ased

co

gnit

ive

dec

line

ove

r 3

yea

rs.

Imp

rove

men

ts w

ere

hig

hes

t in

th

e o

ldes

t o

ld.

Zan

di e

t al

. 2

002

, USA

5

yea

rs

188

9

Mea

n a

ge 7

4.5

ye

ars

Ever

vs.

nev

er

HT

use

an

d F

orm

er v

s.

curr

ent

HT

use

Inci

den

t A

D (

usi

ng

3MS

sco

re)

or

info

rman

t b

ased

qu

esti

on

nai

re

Age

, ed

uca

tio

n, A

PO

E st

atu

s,

his

tory

of

calc

ium

an

d m

ult

ivit

amin

in

take

Pri

or

HT

use

was

pro

tect

ive

agai

nst

A

D t

han

cu

rren

t u

se u

nle

ss la

tter

ex

ceed

ed >

10

yea

rs.

Kan

g et

al.

2

004

, USA

6

yea

rs

138

07

≥

70

yea

rs

Self

-rep

ort

ed

op

po

sed

or

un

op

po

sed

HT

use

TIC

S at

bas

elin

e, v

erb

al

mem

ory

, cat

ego

ry

flu

ency

, dig

it s

pan

b

ackw

ard

s

AP

OE

stat

us,

dem

ogr

aph

ics

and

lif

esty

le f

acto

rs

No

sig

nif

ican

t co

gnit

ive

ben

efit

s w

ere

ob

serv

ed f

or

any

typ

e o

r d

ura

tio

n o

f H

T u

se.

27

Ko

k e

t al

. 2

006

, UK

121

6

bo

rn in

19

46

an

d e

xam

ined

at

age

53

An

nu

al p

ost

al

qu

esti

on

nai

res

bas

ed

info

rmat

ion

on

H

T u

se

Ho

me

visi

ts t

o a

sse

ss

read

ing

spee

d a

nd

co

nce

ntr

atio

n, v

erb

al

mem

ory

Det

aile

d m

eno

pau

se h

isto

ry,

edu

cati

on

, so

cial

cla

ss, s

mo

kin

g,

BM

I, c

ard

iova

scu

lar

dis

ease

Po

stm

eno

pau

sal c

ogn

itiv

e d

eclin

e m

ore

eff

ecti

vely

exp

lain

ed b

y p

rem

eno

pau

sal c

ogn

itiv

e st

atu

s an

d li

feti

me

soci

al c

lass

.

Yaff

e et

al.

200

6, U

SA

2 y

ears

353

7

0-7

9 y

ears

B

ioav

aila

ble

es

trad

iol

(pg/

ml)

Glo

bal

co

gnit

ion

(3M

S),

de

laye

d v

erb

al m

emo

ry,

exec

uti

ve f

un

ctio

n

Age

, rac

e, s

ex,

edu

cati

on

, d

epre

ssio

n, w

eigh

t, h

eigh

t, m

edic

al

his

tory

, HT

pas

t u

se, A

PO

E st

atu

s

Low

er

estr

adio

l lev

els

at b

asel

ine

resu

lte

d in

co

gnit

ive

dec

line

and

ve

rbal

mem

ory

imp

airm

ent.

Pet

itti

et

al.

200

8, U

SA

4 y

ears

290

6

≥7

5 y

ears

Self

-rep

ort

ed

and

pre

scri

pti

on

b

ased

HT

use

An

nu

al c

ogn

itiv

e as

sess

men

t (T

ICS-

m)

A

ge, e

du

cati

on

, rac

e, m

edic

al

his

tory

, tim

e si

nce

men

op

ause

fo

r H

T u

se

Lon

g te

rm H

T u

se w

as n

ot

pro

tect

ive

agai

nst

dem

enti

a.

Pet

itti

et

al.

200

8, U

SA

4 y

ears

29

06

≥

75

yea

rs

Self

-rep

ort

ed H

T u

se a

t b

asel

ine

and

pre

scri

pti

on

b

ased

HT

use

An

nu

al c

ogn

itiv

e as

sess

men

t (T

ICS-

m),

m

edic

al r

eco

rd r

evie

w

Age

, ed

uca

tio

n, r

ace/

eth

nic

ity,

m

edic

al h

isto

ry

No

pro

tect

ive

eff

ects

of

HT

wer

e

ob

serv

ed t

o p

reve

nt

dem

enti

a.

Rya

n e

t al

. 2

009

, Fra

nce

4

yea

rs

313

0

>65

year

s

Cu

rren

t, p

ast,

an

d n

ever

use

rs

of

HT

Du

rati

on

an

d

typ

e o

f H

T u

sed

Glo

bal

fu

nct

ion

, vis

ual

m

emo

ry, v

erb

al f

luen

cy,

verb

al m

emo

ry,

psy

cho

mo

tor

spee

d,

exec

uti

ve f

un

ctio

n

Age

, med

ical

his

tory

, age

at

men

op

ause

, BM

I, e

du

cati

on

, m

arit

al s

tatu

s, d

epre

ssio

n, A

PO

E st

atu

s, c

off

ee in

take

, an

tich

olin

ergi

c d

rugs

Rec

ent

HT

use

imp

rove

d v

erb

al

flu

ency

, wo

rkin

g m

emo

ry a

nd

p

sych

om

oto

r sp

eed

C

urr

ent

HT

use

dec

reas

ed

d

emen

tia

risk

fo

r A

PO

E Ɛ4

car

rier

s o

nly

.

Gre

end

ale

et

al. 2

00

9, U

SA

4 y

ears

234

2

42

-52

yea

rs

Tim

e sp

ent

in

men

op

ausa

l tr

ansi

tio

n a

nd

H

T u

se p

rio

r to

an

d a

fte

r m

eno

pau

se

Pro

cess

ing

spee

d,

verb

al m

emo

ry,

wo

rkin

g m

emo

ry

Age

, sta

ge o

f m

eno

pau

se, r

ace,

ed

uca

tio

n le

vel,

dai

ly li

fe a

ctiv

itie

s,

use

of

lan

guag

e

Co

gnit

ive

dif

ficu

ltie

s d

uri

ng

men

op

ausa

l tra

nsi

tio

n w

ere

re

cove

red

in p

ost

men

op

ause

. H

T u

se p

rio

r to

last

men

stru

al

per

iod

had

ben

efic

ial e

ffec

t th

an

late

r u

se.

Wh

itm

er e

t al

.,

201

1, U

SA

34

yea

rs

55

04

M

idlif

e se

lf-

rep

ort

ed

HT

use

La

te li

fe H

T u

se

asse

sse

d w

ith

p

har

mac

y re

cord

s

Dem

enti

a d

iagn

osi

s fr

om

ele

ctro

nic

med

ical

re

cord

s b

etw

een

19

99-

200

8

Age

, rac

e, e

du

cati

on

, med

ical

h

isto

ry, n

um

ber

of

child

ren

, BM

I W

om

en u

sin

g H

T in

mid

-lif

e w

ere

pro

tect

ed

aga

inst

dem

enti

a.

HT

use

in la

te a

ge w

as d

etri

men

tal.

28

Shao

et

al.

201

2, U

SA

11

yea

rs

176

8

≥ 6

5 y

ears

Ti

me

of

init

iati

on

, d

ura

tio

n a

nd

ty

pe

of

HT

use

d

Co

gnit

ive

imp

airm

ent

(3M

S) a

nd

AD

dem

enti

a (N

INC

S-A

DR

DA

cri

teri

a)

Dem

ogr

aph

ics,

med

ical

an

d

gyn

eco

logi

cal h

isto

ry, l

ifes

tyle

fa

cto

rs

Use

of

HT

wit

hin

5 y

ears

aft

er

men

op

ause

an

d f

or ≥

10

yrs

d

ecre

ased

AD

ris

k.

Op

po

sed

HT

star

ted

>5

yrs

aft

er

men

op

ause

incr

ease

d A

D r

isk

Bo

ve e

t al

. 2

014

, USA

1

8 y

ears

188

4

Mea

n a

ge 7

8

year

s

Self

-rep

ort

ed

info

rmat

ion

on

ty

pe,

du

rati

on

an

d m

od

e o

f H

T u

se a

t b

asel

ine

Dem

enti

a an

d A

D

dia

gno

sis

(NIN

CS-

AD

RD

A),

an

nu

al

cogn

itiv

e te

sts

for

mu

ltip

le d

om

ain

s

Det

aile

d g

ynec

olo

gica

l his

tory

, d

emo

grap

hic

fac

tors

, lif

esty

le

fact

ors

, po

stm

ort

em m

arke

rs o

f A

D

pat

ho

logy

fo

r 6

00 w

om

en

HT

star

ted

wit

hin

5 y

ears

of

per

i-m

eno

pau

sal p

erio

d a

nd

use

d f

or

>10

yea

rs p

rote

cte

d a

gain

st

cogn

itiv

e d

eclin

e.

CA

SE-C

ON

TRO

L an

d C

RO

SS-S

ECTI

ON

AL

STU

DIE

S

War

ing

199

9, U

SA

Cas

e-C

on

tro

l st

ud

y

222

cas

es a

nd

co

ntr

ols

eac

h

mea

n a

ge 5

0

HT

use

as

cert

ain

ed

fro

m r

egi

ster

s

AD

dia

gno

sis

asce

rtai

ned

fro

m

regi

ste

rs

Age

mat

ched

cas

es a

nd

co

ntr

ols

, ed

uca

tio

n, a

ge a

t m

eno

pau

se,

auto

psy

re

po

rts,

bre

ast

and

en

do

met

rial

can

cer,

med

ical

an

d

rep

rod

uct

ive

his

tory

HT

pro

tect

ed a

gain

st A

D

ind

epen

den

t o

f e

du

cati

on

an

d a

ge

at m

eno

pau

se.

Du

ff a

nd

H

amp

son

2

000

, UK

C

ross

sec

tio

nal

st

ud

y

96

4

5-6

5 y

ears

Se

lf r

epo

rte

d H

T u

se

Wo

rkin

g m

emo

ry,

Exp

licit

mem

ory

A

ge, e

du

cati

on

, so

cio

eco

no

mic

st

atu

s m

atch

ed g

rou

ps,

age

at

men

op

ause

, med

ical

his

tory

, typ

e d

ose

an

d s

ched

ule

of

HT

use

HT

use

rs p

erfo

rmed

bet

ter

in b

oth

ve

rbal

an

d s

pat

ial w

ork

ing

mem

ory

ta

sks

than

no

n-u

sers

.

Mak

i et

al.

200

1, U

SA

Cro

ss s

ecti

on

al

184

5

0-8

9 y

ears

O

ral o

r tr

ansd

erm

al

estr

oge

n H

T w

ith

or

wit

ho

ut

pro

gest

ero

ne

Ver

bal

mem

ory

, fig

ura

l m

emo

ry, m

enta

l ro

tati

on

s, a

tten

tio

n,

wo

rkin

g m

emo

ry

Age

, ed

uca

tio

n, a

nn

ual

inco

me,

ty

pe

of

HT,

du

rati

on

of

trea

tmen

t,

self

-rep

ort

ed

hea

lth

sta

tus,

d

epre

ssio

n

HT

use

rs s

core

d s

ign

ific

antl

y b

ette

r th

an n

ever

use

rs in

ver

bal

mem

ory

te

st, e

nco

din

g, a

nd

ret

riev

al o

f w

ord

s.

Bu

ckw

alte

r et

al

. 2

004

, USA

C

ase

-co

ntr

ol

stu

dy

105

≥

75

yea

rs

HT

use

ass

esse

d

fro

m

pre

scri

pti

on

re

gist

er

Lear

nin

g an

d m

emo

ry

(ver

bal

an

d n

on

verb

al,

atte

nti

on

), e

xecu

tive

fu

nct

ion

ing

(wo

rkin

g m

emo

ry, l

angu

age)

Age

, te

lep

ho

ne

inte

rvie

w o

f co

gnit

ive

stat

us

at b

asel

ine,

ed

uca

tio

n, e

thn

icit

y, d

epre

ssio

n,

pas

t H

T u

se a

nd

du

rati

on

HT

no

t b

enef

icia

l in

co

gnit

ive

per

form

ance

am

on

g o

lder

age

gr

ou

p.

Hen

der

son

et

al.

200

5, U

SA

971

wo

men

ag

ed >

60 y

ears

Self

-rep

ort

ed

estr

oge

n u

se

fro

m c

on

tro

ls

and

fro

m

AD

dia

gno

sis

ob

tain

ed

fro

m m

emo

ry c

linic

s A

ge, e

du

cati

on

, eth

nic

ity,

AP

OE

stat

us,

alc

oh

ol i

nta

ke, s

mo

kin

g,

med

ical

his

tory

HT

use

red

uce

d A

D r

isk

amo

ng

you

nge

st a

ge g

rou

p (

50

-63

yea

rs).

29

Cas

e-C

on

tro

l st

ud

y

pri

mar

y in

form

ants

of

AD

cas

es

Ras

gon

et

al.

200

5, S

wed

en

Cro

ss s

ecti

on

al

660

4

twin

s ag

ed 6

5-

84

yea

rs

End

oge

no

us

and

exo

gen

ou

s h

orm

on

e ex

po

sure

Co

gnit

ive

imp

airm

ent

asse

sse

d in

on

e in

terv

iew

th

rou

gh T

ELE,

a

bri

ef t

elep

ho

ne

cogn

itiv

e sc

ree

nin

g te

st

Age

, par

ity,

age

at

men

arch

e an

d

men

op

ause

, len

gth

an

d t

ype

of

HT,

ge

ner

al h

ealt

h, p

hys

ical

act

ivit

y,

occ

up

atio

n, e

du

cati

on

Ris

k o

f co

gnit

ive

imp

airm

ent

dec

reas

ed s

ign

ific

antl

y w

ith

in

crea

se in

len

gth

of

lifet

ime

estr

oge

n e

xpo

sure

.

Mac

Len

nan

et

al.

200

6, A

ust

ralia

C

ross

sec

tio

nal

428

>6

0 ye

ars

Self

rep

ort

ed

HT

use

M

MSE

, att

enti

on

an

d

con

cen

trat

ion

, ver

bal

ex

pre

ssio

n, v

erb

al

lear

nin

g

Age

, ed

uca

tio

n, h

yste

rect

om

y st

atu

s, c

ard

iova

scu

lar

dis

ease

h

isto

ry, B

MI,

sm

oki

ng

an

d a

lco

ho

l in

take

his

tory

, mo

od

Earl

y in

itia

tio

n o

f H

T w

as b

enef

icia

l fo

r se

lect

ive

cogn

itiv

e d

om

ain

s b

ut

late

HT

use

was

det

rim

enta

l.

Gh

ido

ni e

t al

. 2

006

, Ita

ly

Cro

ss s

ecti

on

al

83

wo

men

ag

ed >

50

ye

ars

Cu

rren

t, p

ast

and

nev

er u

se

of

HT

Glo

bal

co

gnit

ion

(M

MSE

), m

emo

ry,

visu

o-s

pat

ial a

bili

ty,

lan

guag

e, in

telli

gen

ce,

atte

nti

on

ass

esse

d in

n

euro

psy

cho

logi

cal t

est

bat

tery

ove

r 6

0-9

0

min

ute

s

Age

, ed

uca

tio

n, d

ura

tio

n o

f H

T (m

on

ths)

, age

at

and

typ

e o

f m

eno

pau

se, f

amily

his

tory

of

dem

enti

a, 4

0 w

om

en u

nd

erw

ent

3D

hig

h r

eso

luti

on

MR

I (to

tal

intr

acra

nia

l vo

lum

e)

Pas

t u

sers

per

form

ed b

ette

r th

an

nev

er u

sers

in li

ngu

isti

c, a

tten

tive

, an

d p

lan

nin

g ab

iliti

es.

Cu

rren

t u

sers

per

form

ed b

ette

r in

ve

rbal

mem

ory

. Es

tro

gen

HT

use

rs h

ad g

reat

er

grey

m

atte

r vo

lum

es t

han

no

nu

sers

Ro

ber

ts e

t al

. 2

006

USA

C

ase

-Co

ntr

ol

stu

dy

264

AD

cas

es

264

co

ntr

ols

M

edic

al r

eco

rds

bas

ed u

se o

f o

ral o

r p

aren

tera

l HT

AD

dia

gno

sis

take

n

fro

m m

edic

al r

eco

rd

linka

ge s

yste

m

Age

at

star

t o

f H

T, t

ime

sin

ce

men

op

ause

, age

at

men

arch

e, t

ype

of

men

op

ause

, rep

rod

uct

ive

span

, m

edic

al h

isto

ry, e

du

cati

on

No

sig

nif

ican

t as

soci

atio

n o

bse

rved

b

etw

een

HT

use

an

d A

D.

W. W

har

ton

et

al. 2

00

9, U

SA

Cas

e-C

on

tro

l st

ud

y

213

5

1-9

3 y

ears

Se

lf r

epo

rte

d H

T u

sers

an

d n

on

-use

rs

Glo

bal

co

gnit

ion

(3M

S),

verb

al f

luen

cy, v

erb

al

mem

ory

(C

ERA

D),

wo

rd

list,

att

enti

on

(St

roo

p

test

) in

1 h

ou

r co

gnit

ive

test

bat

tery

Self

-rep

ort

ed h

ealt

h q

ues

tio

nn

aire

, ag

e, e

du

cati

on

, dep

ress

ion

, alc

oh

ol

inta

ke, s

mo

kin

g, M

MSE

, m

edic

al

his

tory

HT

use

rs p

erfo

rmed

bet

ter

than

n

on

-use

rs o

n m

easu

res

of

verb

al

mem

ory

an

d a

bst

ract

rea

son

ing.

Mak

i et

al.

201

1, A

ust

ralia

C

ross

sec

tio

nal

34

m

ean

age

60

ye

ars

Dai

ly d

iary

b

ased

use

rs a

nd

n

on

-use

rs o

f H

T

Ver

bal

mem

ory

, fac

e m

emo

ry, f

un

ctio

nal

M

RI d

uri

ng

verb

al a

nd

fi

gura

l re

cogn

itio

n

Age

, ed

uca

tio

n, m

oo

d

Wo

men

usi

ng

HT

in

per

imen

op

ause

per

form

ed b

ette

r o

n v

erb

al m

emo

ry t

asks

th

an n

on

-u

sers

an

d it

was

evi

den

t o

n

fun

ctio

nal

MR

I.

30

Wro

olie

et

al.

201

1, U

SA

Cro

ss s

ecti

on

al

stu

dy

68

4

9-6

8 y

ears

at

risk

of

AD

HT

use

as

cert

ain

ed

thro

ugh

p

har

mac

y re

cord

s

Wo

rkin

g m

emo

ry,

pro

cess

ing

spee

d,

verb

al m

emo

ry, v

isu

al

mem

ory

, an

d e

xecu

tive

fu

nct

ion

ing

Ris

k fa

cto

rs o

f A

D, e

du

cati

on

, yea

rs

of

en

do

gen

ou

s e

stro

gen

, age

at

men

op

ause

, BM

I, t

ype

of

men

op

ause

Wo

men

usi

ng

estr

adio

l per

form

ed

bet

ter

in v

erb

al m

emo

ry t

han

CEE

u

sers

.

Hes

son

et

al.

201

2, C

anad

a C

ross

sec

tio

nal

50

M

ean

age

69

.3

Ind

ex o

f cu

mu

lati

ve

estr

oge

n

exp

osu

re (

ICEE

)

Pro

spe

ctiv

e an

d

retr

osp

ecti

ve m

emo

ry,

Logi

cal M

emo

ry in

a

sin

gle

test

ses

sio

n

His

tory

of

HT

use

, age

at

men

arch

e an

d m

eno

pau

se, B

MI,

tim

e si

nce

m

eno

pau

se, n

ulli

par

ity,

du

rati

on

of

bre

ast

feed

ing,

age

, ed

uca

tio

n

ICEE

sig

nif

ican

tly

pre

dic

ted

p

rosp

ecti

ve m

emo

ry t

ask

per

form

ance

bu

t n

ot

retr

osp

ecti

ve

mem

ory

.

Fox

et a

l.

201

3, U

K

Cro

ss s

ecti

on

al

133

7

0-1

00 y

ears

To

tal l

ifet

ime

exp

osu

re t

o

estr

oge

n

(mo

nth

s)

Alz

hei

mer

’s d

emen

tia

asse

sse

d w

ith

Clin

ical

D

emen

tia

Rat

ing

scal

e in

60

-90

min

ute

in

terv

iew

Age

, fam

ily h

isto

ry o

f d

emen

tia,

p

arit

y, a

ge a

t fi

rst

bir

th, a

ny

HT

use

, hys

tere

cto

my,

bila

tera

l o

op

ho

rect

om

y, r

elig

ion

, ed

uca

tio

n,

smo

kin

g, a

lco

ho

l in

take

Lon

ger

rep

rod

uct

ive

span

, age

>2

1

at f

irst

del

iver

y, a

nd

mo

re m

on

ths

in li

feti

me

in p

regn

ancy

wer

e p

rote

ctiv

e ag

ain

st A

D.

Ab

bre

viat

ion

s: A

D:

Alz

hei

mer

’s d

isea

se;

AP

OE:

Ap

olip

op

rote

in E

; 3

MS:

Mo

dif

ied

Min

i Men

tal S

tate

exa

min

atio

n; M

MSE

: Min

i Men

tal S

tate

exa

min

atio

n;

HT:

ho

rmo

ne

ther

apy;

BM

I: b

od

y m

ass

ind

ex; N

INC

S-A

DR

DA

: Nat

ion

al In

stit

ute

of N

euro

logi

c an

d C

om

mu

nic

ativ

e D

iso

rder

s an

d S

tro

ke a

nd

th

e A

lzh

eim

er’s

dis

ease

and

Rel

ate

d D

iso

rder

s A

sso

ciat

ion

; M

RI:

Mag

net

ic r

eso

nan

ce i

mag

ing;

; C

EE:

con

juga

ted

eq

uin

e es

tro

gen

s; C

ERA

D:

Co

nso

rtiu

m t

o E

stab

lish

Reg

iste

r o

f

Alz

hei

mer

’s d

isea

se; T

ICS-

m: T

ele

ph

on

e In

terv

iew

of

Co

gnit

ive

Stat

us-

mo

dif

ied

(TI

CS-

m);

ICEE

: in

dex

of

cum

ula

tive

est

roge

n e

xpo

sure

31

2.6.3 Surgical menopause and HT and AD The impact of HT use after induced menopause is a controversial subject as it depends upon the age at surgical menopause and associated long-term effects. The results from studies on HT use among surgically menopausal women are presented in table 4. An age-dependent risk of dementia and cognitive decline was observed among women undergoing pre-menopausal unilateral or bilateral oophorectomy when they were compared to women without surgery (Rocca et al., 2007). This finding was replicated in a Danish nationwide study, where early onset (<50 years) of surgical menopause increased the risk of dementia (Phung et al., 2010). Similarly, total abdominal hysterectomy and bilateral salpingo-oophorectomy were associated with a significant cognitive decline (Farrag et al., 2002) and women undergoing unilateral oophorectomy before natural menopause had lower cognitive scores than women passing through a natural menopause (Zhou et al., 2011). The use of HT with respect to pre-menopausal surgery improved cognition (Phillips and Sherwin 1992). Short term cross-over trials for use of HT among women with gynecological surgeries either showed improved memory (Moller et al., 2010) or no significant effect on cognition (Schiff et al., 2005, Wolf et al., 2005). Findings from Nurse’s Health Study indicated that ovarian conservation at the time of surgery decreased the risk of cognitive decline (Parker et al., 2009). Important findings from Mayo Clinic Cohort Study of Oophorectomy and Aging revealed that it was critical to consider the time of oophorectomy with respect to the start of HT in this prematurely menopausal group of women (Rocca et al., 2014a). Recent guidelines issued by the American Society of Reproductive Medicine, the Endocrine Society, International Menopause Society, the North American Menopause Society and the British Medical Society recommend that women undergoing early or premature menopause should be prescribed HT until the age of natural menopause to prevent long term health consequences (de Villiers et al., 2013, North American Menopause Society 2012, Panay et al., 2013). The higher risk of cognitive decline among prematurely menopausal women can be due to the following reasons; a direct effect of lack of hormones including estrogen, progesterone, or testosterone; high levels of luteinizing hormone or follicle stimulating hormone; confounding effect of genetic variants which modify the effect of HT on cognition, for example APOE status, smoking, obesity which can interact with each other in a complex way to alter the outcome (Rocca et al., 2009). A recent literature review on the timing hypothesis suggests that estrogen exerts its neuroprotective effects among women undergoing premature menopause long before the onset of natural menopause. Moreover, HT was more beneficial if used in early post-menopause (50-60 years of age) than in late post-menopause (>65 years of age) where HT actually increased the risk of dementia (Rocca et al., 2010, Rocca et al., 2011).

32

Tab

le 4

: St

ud

ies

on

ass

oci

atio

n b

etw

een

su

rgic

al m

eno

pau

se, H

T u

se, a

nd

ris

k o

f co

gnit

ive

dec

line

, dem

enti

a, a

nd

AD

Stu

dy,

co

un

try,

fo

llow

-up

tim

e Sa

mp

le f

eatu

res

Exp

osu

re

Ou

tco

me

Co

vari

ates

M

ain

re

sult

s

Ph

illip

s an

d

Sher

win

1

992

, Can

ada

RC

T 2

mo

nth

s

19

wo

men

wit

h

hys

tere

cto

my

and

b

ilate

ral

oo

ph

ore

cto

my

Mo

nth

ly e

stro

gen

in

ject

ion

s ve

rsu

s p

lace

bo

Imm

edia

te a

nd

del

ayed

re

call

of

visu

al m

ate

rial

, p

arag

rap

hs,

dig

it s

pan

sc

ore

s

Ind

icat

ion

of

surg

ery,

pre

-su

rgic

al, b

loo

d s

amp

les

dra

wn

fo

r p

lasm

a es

tro

ne

and

es

trad

iol l

evel

s

Wo

men

wit

h e

stro

gen

sco

red

b

ette

r p

ost

-su

rger

y co

mp

ared

to

pla

ceb

o t

reat

ed

wo

me

n.

Farr

ag e

t al

. 2

002

, Egy

pt

Clin

ical

sam

ple

6

mo

nth

s

53

(35

wo

men

w

ith

su

rger

y, 1

8

wit

ho

ut

surg

ery

as

con

tro

ls)

Tota

l ab

do

min

al

hys

tere

cto

my

and

b

ilate

ral s

alp

ingo

-o

op

ho

rect

om

y

MM

SE, W

ech

sler

Mem

ory

Sc

ale,

dig

it s

pan

an

d m

enta

l co

ntr

ol,

Au

dit

ory

Eve

nt

rela

ted

po

ten

tial

s

Age

, ed

uca

tio

n, B

MI a

nd

p

arit

y m

atch

ed c

on

tro

ls, a

ge

at m

enar

che,

se

rum

est

rad

iol,

no

pri

or

HT

use

, hea

lth

sta

tus

Sign

ific

ant

cogn

itiv

e d

eclin

e se

en

in w

om

en

un

der

goin

g gy

nec

olo

gica

l su

rger

y co

mp

ared

to

co

ntr

ols

.

Silv

ers

tein

et

al.

200

2, U

SA

Cro

ss s

ecti

on

al

stu

dy

198

8-1

99

1

88

5 w

om

en w

ith

h

isto

ry o

f h

yste

rect

om

y, a

nd

o

op

ho

rect

om

y 6

0-8

9 y

ears

Self

-rep

ort

ed H

T u

se

MM

SE, s

eri

al s

even

s, w

orl

d

bac

kwar

d, b

less

ed

, Tra

ils B

, C

ateg

ory

flu

ency

, Bu

sch

ke

sele

ctiv

e re

min

din

g

Val

idat

ion

of

surg

erie

s fr

om

re

gist

ers

, sm

oki

ng,

alc

oh

ol

inta

ke, e

du

cati

on

, tim

e si

nce

m

eno

pau

se,

No

sig

nif

ican

t d

iffe

ren

ce w

as

ob

serv

ed f

or

wo

me

n u

sin

g H

T af

ter

surg

ery

and

th

ose

no

t u

sin

g H

T.

Sch

iff

et

al.

200

4, U

K

Cro

ss-o

ver

RC

T 2

4 w

eeks

19

wo

men

wit

h

hys

tere

cto

my

>6

0 ye

ars

Tran

sder

mal

es

trad

iol v

ersu

s p

lace

bo

fo

r 1

2

we

eks

then

sw

itch

ing

gro

up

s

Rea

ctio

n t

ime,

vis

ual

tr

acki

ng,

wo

rkin

g m

emo

ry,

imm

edia

te a

nd

del

ayed

vi

sual

mem

ory

Age

, MM

SE a

t b

asel

ine,

rac

e,

pri

or

HT

use

, ser

um

est

rad

iol

leve

ls,

Estr

adio

l im

pro

ved

dep

ress

ive

sy

mp

tom

s.

No

sig

nif

ican

t ef

fect

fo

un

d f

or

cogn

itio

n.

Wo

lf e

t al

. 2

005

, Ger

man

y R

CT

24

wee

ks

35

wo

men

wit

h

hys

tere

cto

my

58

-75

yea

rs

1. O

ral e

stra

dio

l 2

. Ora

l est

rad

iol +

o

ral p

roge

ster

on

e

3. P

lace

bo

Dec

lara

tive

mem

ory

, at

ten

tio

n, v

erb

al f

luen

cy,

men

tal r

ota

tio

n, w

ork

ing

mem

ory

, se

rum

ho

rmo

ne

leve

ls

Age

, BM

I, M

MSE

, ver

bal

kn

ow

led

ge, e

du

cati

on

, age

at

hys

tere

cto

my,

no

t o

n E

T u

se

sin

ce (

year

s),

No

ben

efic

ial e

ffec

t o

bse

rved

fo

r an

y co

gnit

ive

do

mai

n w

ith

an

y tr

eatm

ent.

Ro

cca

et

al.

200

7, U

SA

Cas

e-C

on

tro

l st

ud

y 1

950

-19

87

81

3 (

un

ilate

ral

oo

ph

ore

cto

my)

6

76

(b

ilate

ral

oo

ph

ore

cto

my)

1

,47

2 w

om

en

(co

ntr

ols

)

Pre

-men

op

ausa

l u

nila

tera

l/b

ilate

ral

oo

ph

ore

cto

my

ve

rsu

s co

ntr

ols

w

ith

ou

t su

rger

y

Dir

ect

or

pro

xy in

terv

iew

s b

ased

dem

enti

a o

r co

gnit

ive

imp

airm

ent

dia

gno

sis

Age

at

surg

ery,

ed

uca

tio

n,

his

tory

of

dep

ress

ion

, typ

e o

f in

terv

iew

, in

dic

atio

n o

f su

rger

y

Age

dep

end

ent

risk

of

cogn

itiv

e d

eclin

e o

r d

emen

tia

was

ob

serv

ed a

mo

ng

wo

men

u

nd

ergo

ing

oo

ph

ore

cto

my.

33

Ph

un

g e

t al

. 2

010

, Den

mar

k R

egis

ter-

bas

ed

stu

dy

1

977

-20

06

2,3

13

,38

8 w

om

en

>40

year

s o

ld w

ith

an

d w

ith

ou

t su

rger

y

Hys

tere

cto

my,

o

op

ho

rect

om

y fr

om

N

atio

nal

Pat

ien

t R

egis

ter

Ris

k o

f e

arly

on

set

dem

enti

a fr

om

th

e P

sych

iatr

ic C

entr

al

Res

ear

ch R

egis

ter

Age

at

dem

enti

a d

iagn

osi

s,

det

aile

d g

ynec

olo

gica

l his

tory

, al

coh

ol i

nta

ke, d

epre

ssio

n

dia

gno

sis

Earl

y o

nse

t (<

50

yea

rs)

of

hys

tere

cto

my,

un

ilate

ral o

r b

ilate

ral o

op

ho

rect

om

y w

as

asso

ciat

ed

wit

h in

crea

sed

ris

k o

f d

emen

tia.

Mö

ller

et a

l.

201

0, S

we

den

C

ross

-ove

r R

CT

48

wee

ks

50

su

rgic

ally

m

eno

pau

sal

wo

me

n, m

ean

age

5

4 y

ears

Estr

adio

l val

erat

e +

te

sto

ster

on

e ve

rsu

s es

trad

iol v

aler

ate

+ p

lace

bo

Self

-rep

ort

ed q

ues

tio

nn

aire

b

ased

res

po

nse

to

mem

ory

, ve

rbal

, sp

atia

l ep

iso

dic

m

emo

ry, i

nci

den

tal l

earn

ing

Seru

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34

3. Aims of the study

The main aim of this thesis is to explore the association between use of HT and risk of

AD, dementia, and cognitive decline in different population-based and National

Finnish studies i.e. the Medication and Alzheimer’s disease (MEDALZ); Kuopio

Osteoporosis Risk Factors and Prevention (OSTPRE) cohort study; and

Cardiovascular Risk Factors and Dementia (CAIDE) study cohort. The specific aims

of this thesis are:

1. To assess whether oophorectomy, hysterectomy and hysterectomy with

bilateral oophorectomy are related to the risk of AD, whether the possible

indication for surgery plays a role, and if this association is modified by the use

of HT (MEDALZ-2005; Study 1).

2. To explore the association between self-reported and register-based

postmenopausal HT and the risk of AD in a large population-based cohort

(OSTPRE; Study 2)

3. To evaluate the longitudinal association between self-reported HT use and

cognition in a population-based cohort while controlling for midlife risk factors

and APOE Ɛ4 status (CAIDE; Study 3)

4. To study the association between register-ascertained postmenopausal HT use

and the risk of AD in a nationwide nested case-control study (MEDALZ; Study

4)

35

4. Subjects and Methods

4.1 MEDICINE AND ALZHEIMER’S DISEASE (MEDALZ) (STUDY 1

AND 4)

4.1.1 Study population and design Study 1 of this thesis is based on the MEDALZ-2005 population, which is a case control study and includes all community-dwelling women with a clinically verified AD diagnosis, residing in Finland on 31st December 2005 (n=19,043). Cases were identified from the Special Reimbursement Register and an age, gender, and region of residence matched control was assigned to each case (n of matched case control pairs= 19,043). The age range of women was 42-101 years and the follow-up period was from 1986-2005. Study 4 (MEDALZ) has many similarities to MEDALZ-2005, but it includes those who received a clinically verified AD diagnosis between 2005-2011, and one to four age-, sex- and region of residence- matched comparison persons for each individual with AD (n of cases=70,719, n of controls 282,862, N =353,581). The age range of the cohort was 34-105 years (mean 80.1 (SD 7.1) years) and 246,117 (65.2%) of the sample were women. Our study comprises of 230,580 women (n of AD cases=46,117 and n of controls= 184,463) with a follow-up period from 1995-2011. Controls were identified from the register that contains all residents of Finland who are entitled to benefits from the Social Insurance Institution, i.e. all citizens and residents living in Finland for at least two years. Each resident of Finland is assigned a unique social security number which was used to link the participant’s data to national Hospital Discharge Register.

4.1.2 Exposure data For study 1, data on bilateral oophorectomy, hysterectomies, and hysterectomy in combination with bilateral oophorectomy during 1986-2005 was obtained from the National Hospital Discharge Register. Surgeries occurring after AD diagnosis were not taken into account. From 1996-2005, we used Nordic Medico-Statistical Committee’s Classification of Surgical Procedures (NOMESCO) codes for operations [NOMESCO-2010]. During 1986-1995, we used the corresponding codes from the Finnish Classification system. As a malignant neoplasm is one of the indications for these surgeries, we analyzed the association of gynecological surgeries and AD separately in women with and without history of malignant neoplasm of cervix uteri, corpus uteri, uterus, or ovary with the following codes from the International Classification of Disease (ICD-10 codes C53-C56 and C57.0 and the corresponding ICD-9 and ICD-8 codes). Data on these diagnoses was taken from the hospital discharge register (years 1986-2005) (Figure 4).

36

Figure 4: Prevalence of surgery (%) among cases and controls in the MEDALZ-2005 study from 1986-2005 (study 1)

Data on HT use from 1995-2005 for study 1 and from 1995-2011 for study 4 were extracted from the National Prescription Register which contains information about the drugs dispensed at pharmacies to all Finnish residents living in non-institutionalized settings since 1995 and is maintained by the Social Insurance Institution. The following Anatomical Therapeutic Chemical (ATC) codes were used to identify the drugs: G03C (estrogen), GO3D (progestogen), G03F (estrogen and progestogen in combination), and G03X (other sex hormones and modulators of genital system) (Figure 5). Only systemic HT (oral or transdermal) was taken into account. Based on the register records, we were able to categorize HT use into (never users, users 1-5 yrs, users for 6-9 yrs and users for 10-11 yrs) for study 1 and (never users, users for 1-5 yrs, 6-9 yr users and users for >10 yrs) for study 4. Type and mode of HT use were available for study 4 but not for study 1. In both studies, the purchase data from prescription register was modelled to periods of use by a decision procedure that included each person’s purchase history for each ATC code, processed in a chronological order. The method constructs exposure time-periods and estimates the dose used during that period by considering the purchased amount in defined daily doses. This method takes into account stockpiling of drugs, personal purchasing patterns i.e. regularity of the purchases, and periods of hospital or nursing home care where drug use is not recorded in the prescription register (Tanskanen 2015).

3,69%

4,24%

6,69%

7,49%

3,21%3,69%

AD cases (n=19,043) Controls (n= 19,043)

Bilateral oophorectomy Hysterectomy Hysterectomy with bilateral oophorectmy

37

Figure 5: Use of HT (%) among cases and controls in MEDALZ population (study 4)

4.1.3 Outcome data Persons with AD in both studies were identified from the Finnish Special Reimbursement Register maintained by the Social Insurance Institution. The Special Reimbursement Register contains records of all persons who are eligible for higher reimbursement due to certain chronic diseases; this includes AD. To be eligible for reimbursement, the disease must be diagnosed according to specific criteria and a diagnosis statement must be submitted to the Social Insurance Institution by a physician. The specific criteria for a verified AD diagnosis are 1) symptoms consistent with mild or moderate AD, 2) a decrease in social capacity over a period of at least 3 months, 3) a computer tomography/magnetic resonance imaging scan, 4) exclusion of possible alternative diagnoses, and 5) confirmation of the diagnosis by a registered neurologist or geriatrician. Diagnosis of probable AD was based on the NINCDS-ADRDA and DSM-IV criteria.

4.1.4 Covariables A co-morbidity score was calculated for both studies using the Charlson Comorbidity Index as a reference. For study 1, information on chronic diseases was taken from the Special Reimbursement Register. The modified Comorbidity score for study 1 was calculated using the following diseases with corresponding scores; heart failure, coronary artery disease, type 1 or 2 diabetes, chronic asthma or chronic obstructive pulmonary disease, disseminated connective tissue diseases, rheumatoid arthritis and other comparable conditions (score of 1); uremia requiring dialysis, severe anemia in connection with chronic renal failure, leukemia, other malignant diseases of blood and bone marrow including malignant diseases of the lymphatic system, and all cancers (score of 2). Due to the skewed distribution, the score was categorized to “0”, “1”, “2”, and “3” or more and modeled as an ordinal variable. For study 4, data on co-morbidities from 1972 until 5 years before the AD diagnosis of index case were extracted from the Hospital Discharge Register. To avoid collinearity,

19,99%18,38%

11,66%10,60%

AD cases (n= 46,117) Controls (n= 184,463)

Any estrogen use Any progestogen use

38

a composite score was derived for those predictors that were associated with the risk of AD in this cohort as follows: cancer, pancreatic insufficiency and renal insufficiency were scored as -1; peripheral vascular disease, asthma/chronic obstructive pulmonary disease, diabetes, cardiac arrhythmia, mental and behavioral disorders, ischemic heart disease, stroke, hemiplegic, anemia, and liver disease as 1; alcohol abuse, psychosis, fluid and electrolyte disorders, and weight loss as 2; and epilepsy as 3. The scores were summed together to derive an overall index, with higher values indicating higher risk of AD. Socioeconomic status was estimated from the censuses maintained by Statistics Finland based on occupational social class and was available only for study 4. The data was collected at 5 year intervals starting from 1970 until 2000, and annually from 2004 onwards. Based on the associations between original socioeconomic categories and AD, socioeconomic status was categorized into 6 classes. For each individual, the highest class from 1970 until 5 years before AD diagnosis was used (Tolppanen et al., 2016).

4.2 KUOPIO OSTEOPOROSIS RISK FACTORS AND PREVENTION COHORT (OSTPRE) (STUDY 2)

4.2.1 Study population and design Study 2 of this thesis is based on the 20 years’ postal questionnaire based follow-up of the population of the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort (Figure 6). The first self-administered baseline postal questionnaire was sent to all women aged 47-56 years who were residents of Kuopio Province, Eastern Finland (n= 14 220) in February 1989. A total of 13 100 (92.1%) women responded. Subsequently the 5 year follow-up in 1994, 10 year follow-up in 1999, 15 year follow-up in 2004, and 20 year follow-up in 2009 were mailed to the 13 100, 12 562, 12 075, and 11 420 women respectively. A total of 11 954 (91.2%), 11 538 (91.8%), 10 926 (90.4%) and 8195 (71.8%) women responded to the 5, 10, 15, and 20 year follow ups respectively. The questionnaires were sent to women who had responded to the baseline inquiry, were alive, and had a valid postal address at that time (Figure 7).

39

Figure 6: Flow-chart of the Kuopio Osteoporosis risk factors and Prevention cohort (OSTPRE) The study population of the present study included those 8195 women for whom we had complete data on confounders and self-reported HT exposure. Outcome data and register-based exposure data were available for all participants (Figure 7).

Figure 7: Study population of Kuopio Osteoporosis Risk Factors and Prevention Cohort

(Study 2)

0

2 000

4 000

6 000

8 000

10 000

12 000

14 000

16 000

1989 1994 1999 2004 2009

Sent 14 220 13 100 12 562 12 075 11 420

Received 13 100 11 954 11 538 10 926 8195

Nu

mb

er o

f q

ues

tio

nn

aire

sPostal questionnaire sent to all 47-56 year

old women who were resident of Kuopio

Province in February 1989 (n=14,220)

Returned Baseline questionnaire

n= 13,100

Study 2 sample (n=8195)

Baseline questionnaire

not obtained (n=1120)

Missing data on any

confounder, n=4905

Sensitivity analysis among those

with data on education, n= 2383

40

4.2.2 Exposure data

In examining the association of postmenopausal HT use with risk of AD, data on HT use was collected in two ways; first, self-reported HT use was taken from self-administered questionnaires over 20 years; second, HT use was ascertained from registers. Self-reported HT use was recorded as lifetime use in years (and indication of use) at the baseline inquiry in 1989. In all follow-up questionnaires, numbers of months per year of estrogen use were reported and the duration of self-reported estrogen use was calculated on the basis of these questionnaires. Self-reported use of estrogen was categorized into post-menopausal HT based on the use after the onset of the menopause. In order to exclude the possibility of recall bias in the self-reported questionnaires, we accessed the prescription register data to ascertain HT use. HT was defined from the registry as those preparations having systemic estrogenic properties belonging to the following codes in the ATC classification: G03C (estrogens), G03F (estrogen and progesterone) excluding oral contraceptives. Duration of medication (HT) use was calculated based on prescription purchased data. ATC codes for each purchase history were processed for each individual. Purchase history was used to calculate defined daily dose which could be used to determine exposure period for each drug. The prescription register does not cover drugs used in public nursing homes or during stay in hospitals (Tolppanen et al., 2016).

4.2.3 Outcome data The main outcome of study 2 was a clinically verified AD diagnosis. These diagnoses from the years 1999-2009 were identified from the Finnish Special Reimbursement Register maintained by the Social Insurance Institution. The contents of the register have been described above. A sensitivity analysis with any dementia as an outcome was also performed. Dementia diagnoses were extracted from the National Hospital Discharge register using the following ICD-10 codes: F00-03 (F00-Dementia in Alzheimer’s disease; F01-vascular dementia; F02-Dementia in other diseases classified elsewhere; F03-Unspecified dementia) and G30 (Alzheimer’s disease-early/late onset). This register includes all inpatient admissions, as mandated by law. Main and auxiliary diagnosis codes for each admission had been made by the attending physician. All Finnish citizens/long-term residents are covered by tax-supported public health service so the coverage is not restricted by non-medical factors e.g. ability to pay for medications.

4.2.4 Covariables Data on BMI, menopause status, physical activity, education, smoking, occupation status, alcohol use, and health disorders diagnosed by a physician, and gynecological history were inquired in baseline questionnaires and then repeated in all of the following questionnaires. A woman was considered postmenopausal if ≥ 12 months had passed since her last natural menstrual cycle; if she had undergone surgical menopause through bilateral oophorectomy with or without hysterectomy; or if the time since menopause and the history of HT use could be clarified from the follow-up questionnaire. BMI was calculated as the ratio of weight in kilograms to height in meters squared. Physical activity was inquired through self-reported data in three ways at baseline and in all follow-up surveys as: leisure time physical activity as well as asking about how

41

physically demanding their work had been in the last year; ambulatory status as capability and extent of movement, need of aids in movement, and history of joint degeneration; amount of physical activity including winter and summer activities, amount of current regular physical activity and its duration (hours per week). Data on education was available from a sub-cohort only; these individuals had undergone a bone mineral density measurement (n=2383). History of ever/never smoking was asked in all self-reported questionnaires along with regularity of smoking, number of years of smoking, and number of cigarettes smoked per day. Data on occupation was gathered under 9 different categories but then dichotomized into “employed” and “unemployed”. Alcohol consumption was inquired as the amount of alcohol beverages consumed during a one-month period and converted into grams of alcohol intake per month. At baseline, women were asked about the age at menarche, age at menopause, number of pregnancies, number of live births, and abortions. Abortion was inquired in questionnaire as “Number of times to interrupt pregnancies due to abortion/miscarriage”. A history of any gynecological operations (caesarian sections and sterilizations) was also obtained, as well as what, if anything, had been removed in these operations (uterus, ovary, part of both, cervix, or other parts of genitals).

4.3 CARDIOVASCULAR RISK FACTORS, AGING AND DEMENTIA (CAIDE) COHORT STUDY (STUDY 3)

4.3.1 Study population and design CAIDE is a longitudinal, population-based study carried out in Eastern Finland. The participants were examined in midlife within the framework of the North Karelia project and the FINMONICA (Finnish Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) study in 1972, 1977, 1982 or 1987. Individuals who were still alive, aged 65-79 years, and living in the areas of Kuopio and Joensuu in Finland at the end of 1997 were invited to the first re-examination in 1998 (baseline visit for study 3). A second re-examination of same cohort was conducted in 2005-2008 (follow-up visit for study 3). Both re-examinations included a self-administered questionnaire on sociodemographic characteristics, health-related behaviors, and medical history. Specially trained nurses ensured that questionnaires were fully completed (Figure 8). A three-step protocol for dementia diagnosis was applied at both re-examinations: screening phase, clinical phase, and differential diagnostic phase. In 1998, participants with ≤ 24 points on the MMSE at screening were referred to the clinical phase for further examinations. In 2005-2008, participants with ≤ 24 points on MMSE, or with a decrease of ≥3 points on MMSE since 1998, or with < 70% delayed recall in the CERAD word list, or with informant concerns regarding the participant’s cognition were referred to the clinical phase. The clinical phase involved comprehensive neurological, cardiovascular, and neuropsychological examinations. The differential diagnostic phase included brain imaging (MRI/CT), blood tests, cerebrospinal fluid analysis if needed, and electrocardiogram. A review board consisting of the physician, neuropsychologist, and a senior neurologist ascertained the primary diagnosis based on all information. Dementia was diagnosed using the DSM-IV criteria. For Alzheimer's disease, the diagnostic criteria of the NINCS-ADRDA were used. For mild cognitive impairment, a modified version of the Mayo Clinic Alzheimer’s Disease Research Center criteria

42

was used. The present study comprised women from the CAIDE cohort without dementia or MCI at the first re-examination in 1998, and who responded to the HT use questionnaire in 1998 (n=731). The mean follow-up time between the first and the second re-examination for this CAIDE subsample was 8.3 years. Figure 8: Flow-chart of CAIDE participants (women) included in Study 3

4.3.2 Exposure data HT use was measured with a self-administered questionnaire in 1998: “How long have you been using HT during your life?” Self-reported HT use (n=731) was classified as follows: never use (N=488), use for ≤5 years (N=116), and >5 years (N=127).

4.3.3 Outcome data Outcome of interest in our study was cognitive decline. A comprehensive battery of neuropsychological tests was carried out to assess several cognitive domains. Tests used in both 1998 and 2005-2008 examinations included: (1) Mini Mental Scale Examination as a measure of global cognition; (2) immediate word recall test (one word list) for episodic memory; (3) The Stroop test (the time difference between the color word interference and naming tasks) to assess executive functioning; (4) Verbal expression assessed by category fluency test; (5) Bimanual Purdue Pegboard Test and the letter digit substitution test, with the mean of their normalized scores as a measure of psychomotor speed. A change in continuous scores of cognitive tests between 1998 and 2005-2008 was used as outcome data.

4.3.4 Covariables The history of gynecological surgery was inquired in the self-report questionnaire. A comorbidity index was calculated using the Charlson Comorbidity Index as a reference. Data on medical conditions diagnosed until the re-examination visit in 1998

Invited random sample (Kuopio, Joensuu)

Women N=1250

n=2000

Participants N=900

Completed cognitive assessments N= 875

HT & cognition in 1998 analyses N=731

HT & cognition in 2005-2008 analyses N=453

Non-participants N=350

2nd

examination

(2005–2008)

Non-participants N=278

Excluded: MCI N=55; dementia N=35; missing data on exposure or confounders N=54

1st

examination

1998

43

were obtained from the Finnish Hospital Discharge Register. The comorbidity index was calculated based on available data about the following conditions and corresponding scores: myocardial infarction, heart failure, coronary heart disease, stroke/transient ischemic attacks, diabetes, asthma or chronic obstructive pulmonary disease (score of 1); kidney failure and malignant neoplasms (score of 2). APOE genotype was assessed from blood leucocytes using polymerase chain reaction and Hhal digestion. Women were classified as APOE Ɛ4 carriers and non-carriers.

4.4 STATISTICAL ANALYSES

4.4.1 Study 1 Study 1 focused on the association between oophorectomy, hysterectomy, and radical hysterectomy and AD. Statistical analyses were performed with Stata 12.0 (Stata Corp LP, College Station, TX). Between-group differences in the age at surgeries were assessed with Kruskal-Wallis test and differences in age at cohort definition (December 31, 2005) with Student’s t-test. The association between use of HT, surgery and AD was analyzed by chi-square test. To account for matched design, odds ratio (OR) and 95% confidence interval (CI) for AD were calculated with conditional logistic regression. The associations of surgical procedures were adjusted for comorbidity index and use of HT while surgical procedures, uterine/ovarian cancer and comorbidity index were taken into account when the association of HT with AD was investigated. We considered only those gynecological surgeries, diagnoses and HT that occurred before the AD diagnosis, but also performed sensitivity analyses excluding those pairs where the exposure (HT or surgery) occurred less than 5 years before the AD diagnosis.

4.4.2 Study 2 Statistical analysis for study 2 was carried out with Stata 12.0 (Stata Corp LP, College Station, TX). The characteristics of women with respect to AD incidence were compared using the chi-square test for categorical variables and t-test for continuous variables. Correlation between confounders and exposure were investigated with the Spearman correlation coefficient. As expected, hysterectomy and oophorectomy were strongly correlated (r=0.561) and were thus combined into one variable “surgery”. There were no other indications of collinearity (r<0.4). Cox proportional hazard models were used to evaluate the association between HT use and AD incidence. Separate analyses were carried out for different durations of use and different types of HT. Hazard ratios (HR) and 95% confidence interval CI were estimated for 3 different models: model 1 was adjusted for age; model 2 was adjusted for age, BMI, alcohol, smoking, physical activity and occupation status; while model 3 controlled for all variables used in model 2 along with the number of births, menopause status, any cancer, and surgery. Since the education data was available only for a subset of participants, sensitivity analyses were conducted in this group separately. Association between HT and dementia were studied similarly.

4.4.3 Study 3 Cognitive test scores were log-transformed because of skewed distribution. Continuous variables are presented as medians with 95% CI and their range (minimum-maximum). The associations between categorical variables and categories

44

of HT use by duration were assessed by chi-square tests and between continuous variables and HT use by linear regression. The associations between HT categories and cognitive tests at baseline and follow-up examination (8.3 years later) were investigated with multivariable linear regression, with non-users as reference category. Model 1 was adjusted for age, education, and APOE status. Model 2 was additionally adjusted for hysterectomy and co-morbidity index. The analyses of cognitive test performance in follow-up examination were adjusted for follow-up time and cognition at baseline examination. Secondary analysis were carried out for register recorded data on the type of HT from 1995-1998, and this data was stratified by the type of gynecological surgery as well. The results were presented as beta coefficients with p-values. Data was analyzed using Stata 12.0 (Stata Corp LP, College Station, TX).

4.4.4 Study 4 Statistical analyses were conducted with STATA 14.0 (Stata Corp LP, College Station, TX USA). The association of exposures and AD were assessed with conditional logistic regression that accounted for matching. Effect modification by sex and age was assessed by modelling the statistical interaction for these factors and head injury or TBI. Between-group differences in the age at surgeries were assessed with Kruskal-Wallis test and differences in age at cohort definition (2005-2011) with Student’s t-test. The association between use of HT, surgery and AD were analyzed by chi-square test. To account for matched design, OR and 95%CI for AD were calculated with conditional logistic regression. The associations of HT with AD were adjusted for socioeconomic status, co-morbidities, surgeries, and gynecological cancer. HT that occurred until 5 years before the AD diagnosis was considered to avoid survival bias, but sensitivity analyses were also performed for those pairs without any gap between exposure (HT) and outcome (AD diagnosis).

45

5. RESULTS

5.1 BASELINE CHARACTERISTICS OF STUDY POPULATION

Table 5 describes the main characteristics of the population from all studies. Studies 1 and 4 were nationwide nested case control studies with 19,046 and 46,117 AD cases respectively and studies 2 and 3 were regional cohort studies where the main outcomes were AD and cognitive decline respectively. The Finnish Special Reimbursement Register was used to ascertain cases of probable AD in studies 1, 2 and 4. The average age at AD diagnosis was 81, 72.3, and 81.5 years in studies 1, 2 and 4 respectively and women in all studies were mainly postmenopausal. The mean follow-up time was different for all studies, for cohort studies, it varied from 8.3 years for CAIDE to 20 years for OSTPRE; while case-control studies relied on availability of relevant data from registers spanning 1986-2005 for gynecological surgeries and 1995-2011 for HT use in study 1 and 1986-2011 for gynecological surgeries and 1995-2011 for HT use in study 4. HT use was examined for the association with AD in studies 2, 3 and 4 while surgical removal of uterus and ovary was the main exposure for study 1 along with indication of gynecological surgery and HT use as effect modifiers. Women with AD in study 4 underwent any form of gynecological surgery (oophorectomy, hysterectomy, and radical hysterectomy) more often than women in study 1. In study 1, AD cases had gynecological surgery at a relatively younger age than controls and all surgeries were performed in the postmenopausal period i.e. >60 years. HT use was ascertained for case-control studies from prescription registers while it was self-reported in the OSTPRE and CAIDE studies. In OSTPRE, register-ascertained HT use was also studied. No information was available about the type of HT used in CAIDE, while in all other studies, estrogen and combination HT use was studied. The cognitive decline was tested at two time points in CAIDE with respect to HT use, no information for cognitive domains was available from the other three studies. The main route of HT administration in all studies was oral, use of oral contraceptives was excluded for OSTPRE and considering the age range of the participants, it does not seem to be a possible indication of HT use in the three other studies. No information was available about the start of HT with respect to menopause status, though age ranges of study populations imply that the women were mainly post-menopausal. Data on APOE status was available only for CAIDE. In study 3, based on the response to HT use questionnaire in 1998, 243 women had used HT in total at baseline, 116 used for ≤5 years and 127 for >5 years, while in follow-up, total HT users were 169; 76 for <5 years and 93 for >5 years. APOE status and comorbidity index was not associated with HT use at baseline. Women using HT for >5 years were younger, had longer formal education, and underwent hysterectomy more frequently than never and short-term HT users. Long term HT users had better scores in global cognition, episodic memory, and psychomotor speed tests in 1998 baseline than short term users or non-users. The association between long-term use and better global cognition and psychomotor speed remained during follow-up.

46

Table 5: Main characteristics of study population in all studies

Characteristics MEDALZ-2005

(Study 1)

OSTPRE

(Study 2)

CAIDE

(Study 3)

MEDALZ

(Study 4)

Study type Case-control Cohort Cohort Case-control

Sample size 38,086 8195 731 230,580

Number of

cases/with cognitive

decline for study 3

19,043 277 1998: 731 and 2005-

2008: 453

46,117

Follow up time 1986-2005 20 years 8.3 years 1995-2011

Age At time of AD

diagnosis: 81 (77-

85)

At baseline: AD

cases 54.1 (51.4-

56.0)

AD (no): 52.0

(49.6-47.3)

In 1998: HT non

users: 70.8 (70.3-

71.5)

HT users >5 years:

68.8 (67.9-69.7)

At time of AD

diagnosis: 81.5

(76.8-85.4)

Main exposure Surgery

(Oophorectomy,

hysterectomy)

HT use HT use HT use

Source of exposure Register based

(National hospital

discharge register)

Self-reported &

register based

(National

prescription

register)

Self-reported Register based

(National

prescription

register)

Type of HT Estrogen,

Combination,

Other

Estrogen,

combination,

excluding oral

contraceptives

Any HT Estrogen,

progesterone,

combination

Mode of HT use Oral , transdermal Oral, plaster, gel Oral Oral,

transdermal

Time of initiation of

HT with respect to

menopause

NA NA NA NA

Bilateral

oophorectomy (%)

AD cases: 3.69%

Controls: 4.24%

AD cases: 0.36 %

No AD: 1.48 %

NA AD cases: 4.15%

Controls: 3.50%

Hysterectomy (%) AD cases: 6.69%

Controls: 7.49%

AD cases: 18.41 %

No AD: 15.95 %

HT non users: 5 %

HT users >5 years:

12.7 %

AD cases: 7.13%

Controls: 5.78%

Hysterectomy with

bilateral

oophorectomy (%)

AD cases: 3.21%

Controls: 3.69%

AD cases: 14.08 %

No AD: 13.59 %

HT non users: 11.9

%

HT users >5 years:

27.8 %

AD cases: 3.52%

Controls: 3.01%

Age at

oophorectomy

Median

(interquartile range)

AD cases: 67 (60.6-

72.3)

Controls: 68 (61.2-

73.8)

NA NA NA

Age at hysterectomy

Median

(interquartile range)

AD cases: 68 (61.5-

73.5)

Controls: 69 (62.3-

74.8)

NA NA NA

47

Cancer of

uterus/ovary/cervix

AD cases: 1.83%

Controls: 2.09%

AD cases: 13.36

No AD: 13.15

NA AD cases: 1.85%

Controls: 1.84%

Main outcome AD AD Cognitive decline AD

Source of outcome Register based

(special

reimbursement

register)

Register based

(special

reimbursement

register)

Cognitive test

battery by trained

person

Register based

(special

reimbursement

register)

Diagnostic criteria

for main outcome /

main outcome

measures

NINCS-ADRDA

DSM-IV for

probable AD

NINCS-ADRDA

DSM-IV for

probable AD

1 Change in

cognitive tests

(MMSE, immediate

word recall test,

The Stroop test,

Category fluency

test, Bimanual

Purdue Pegboard

Test and the letter

digit substitution

test)

NINCS-ADRDA

DSM-IV for

probable AD

APO E status NA NA Yes NA

Co-variables Modified Charlson

comorbidity index,

uterine/ovarian

cancer, use and

duration of HT

Age, BMI, alcohol

use, smoking,

physical activity,

occupation

status, number of

births,

pregnancies,

abortions,

education,

menopause

status, any

cancer,

oophorectomy,

hysterectomy

Education,

hysterectomy,

ApoE status,

Comorbidity index

and at second

follow-up adjusted

for follow-up time

and also cognition

at first re-

examination

Socioeconomic

status, co

morbidities,

oophorectomy,

hysterectomy,

gynecological

cancer

Abbreviations: AD: Alzheimer’s disease; MEDALZ: Medicine and Alzheimer’s disease; OSTPRE:

Osteoporosis Risk Factors and Prevention study; NA: not available; NINCS-ADRDA: National Institute of

Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders

Association; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders 4th; BMI: body mass index; APOE:

Apolipoprotein E; HT: hormone therapy; MMSE: Mini Mental State Examinatio

1 A change in continuous scores of cognitive tests between 1998 and 2005-2008 was used to assess

cognitive status.

48

5.2 OOPHORECTOMY, HYSTERECTOMY, RADICAL HYSTERECTOMY AND AD

Table 6 depicts the risk of AD among women undergoing any surgery along with the underlying indication of surgery in study 1. The vast majority, 91.8 %, of women in this study were older than 51 years, so the most likely indication for surgery at this age is cancer, which itself decreases AD incidence due to a survival bias. To assess whether this would explain the results, the risk of AD was estimated separately for those with (n=740) and without a history of gynecological cancer (37,340) in the whole sample. The total number of women undergoing oophorectomy in whole sample was 1510, among them 387 (25.6%) had cancer, while the majority (74.4%) did not have cancer. Though women undergoing gynecological surgery were relatively younger than women without surgery; age at oophorectomy/hysterectomy was not related to the risk of AD (all P-values ≥0.23). As the results show, women undergoing any gynecological surgery without any history of malignancy had a lower risk of AD than women undergoing surgery due to malignancy i.e. there was an 11% less AD risk was seen with hysterectomy, and almost 14% less AD risk was observed among women having oophorectomy and radical hysterectomy while controlling for HT use and co-morbidities. No association was seen in surgery and AD among women with a history of malignancy, although the size of this group was rather small. After excluding those pairs with <5 years between the surgery and AD diagnosis, the results in women with no cancer history remained same but the point estimate among women with a history of malignancy was closer to one (not shown here). Thus, it is unlikely that our results are explained by AD affecting the likelihood of gynecological surgery, i.e. women with symptoms of AD having lower likelihood of undergoing hysterectomy or oophorectomy.

Table 6: Association between surgical procedures and risk of AD in women with (n=740) and

without (n=37,340) history of malignant neoplasms of uterus/ovaries/cervix (Study 1)

Exposure Model 1 (unadjusted) Model 2 (adjusted)*

OR (95% CI) P OR (95% CI) P

History of malignant neoplasms

No surgery 1.00(reference) 1.00 (reference)

Oophorectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43

Hysterectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43

Radical Hysterectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43

No history of malignant neoplasms

No surgery 1.00 (reference) 1.00 (reference)

Oophorectomy 0.85 (0.76–0.96) 0.010 0.85 (0.75–0.97) 0.013

Hysterectomy 0.90 (0.82–0.98) 0.012 0.89 (0.81–0.97) 0.008

Radical Hysterectomy 0.87 (0.76–0.99) 0.033 0.85 (0.75–0.98) 0.024

*Adjusted for use and duration of HT and modified Charlson comorbidity index

49

5.3 HT USE AND AD

The association between use of HT and risk of AD was explored in three studies of this thesis and the results are summarized in table 7. Though the main exposure in study 1 was gynecological surgery, we also investigated the association between HT use and AD. The longest duration (10-11 years) of HT use was associated with a lower risk of AD, even after controlling for surgery and co-morbidities. With respect to the type of HT, both estrogen and combination HT use was related to a higher AD risk while hormone therapy in others category was not associated with AD. The majority of HT users used estrogen in combination, with few (n=183) using other forms of (progesterone or other sex hormones and modulators of genital system) HT. In OSTPRE study, the status of HT use was available from two sources; self-reported over 20 years and register-based for almost 15 years. Neither self-reported nor register based HT use was associated significantly with a relative risk of AD. The women were mainly postmenopausal in this study. When the type of HT was taken into consideration, none of the various types of HT was associated with AD both in registers and self-reported HT documentation. Data on education was available only for part of the cohort (n=2383), and results for HT and AD association were similar also in this group and further adjustment for education did not affect the results or conclusions. The longest duration (>10 years) of self-reported estrogen use was related to a lower relative risk of AD in comparison to never-users, even after controlling for lifestyle variables related to estrogen status. The results listed in table 7 include women with probable AD diagnosis only, but sensitivity analyses with any dementia as an outcome (data not shown) gave similar results. Data on the use of HT was available for a longer duration in study 4 than in study 1. In addition, due to the more sophisticated modelling of the exposure, we had information on type, mode and duration of HT use for study 4. No specific type and mode of HT use was associated with AD risk, except that short term oral estrogen and progesterone use was associated with an increased risk of AD. With respect to the duration of HT use, up to 10 years of estrogen, progesterone and combination HT use increased the risk of AD, while 10 years or more of estrogen use decreased the risk whereas 10 years or more of progesterone and combination HT use had no significant effect on the AD risk in the fully adjusted model. Long term use of estrogen monotherapy was associated with a lower risk of AD, while long term progesterone monotherapy was associated with an increased risk of AD.

Table 7: Association between use of HT and risk of AD (Study 1, 2, and 4)

Use of HT Unadjusted model* Fully adjusted model**

Study 1 (MEDALZ-2005) OR (95% CI) P OR (95% CI) P

Duration of HT No HT 1.00 (reference) 1.00 (reference)

HT (1-5 years) 1.30 (1.21-1.41) <0.001 1.32 (1.22-1.43) <0.001 HT (6-9 years) 1.60 (1.48-1.81) <0.001 1.66 (1.51-1.84) <0.001

HT (10-11 years) 0.38 (0.32-0.44) <0.001 0.39 (0.33-0.45) <0.001 Type of HT

None 1.00 (reference) 1.00 (reference) Estrogen only (G03C) 1.09 (1.01-1.18) 0.036 1.12 (1.03-1.22) 0.008

Combination (G03F or G03C & G03D)

1.22 (1.09-1.37) 0.001 1.22 (1.08-1.37) 0.001

Others 0.95 (0.70-1.27) 0.710 0.94 (0.70-1.26) 0.677

50

Study 2 (OSTPRE) HR (95% CI) P HR (95% CI) P

Duration of postmenopausal HT use (self-reported)

None 1.00 (reference) 1.00 (reference) <1 year 1.1 (0.69–1.8) 0.607 1.1 (0.69–1.8) 0.644

1-3 years 1.1 (0.76–1.5) 0.670 1.0 (0.72–1.5) 0.881 3-5 years 1.2 (0.76–1.8) 0.467 1.1 (0.73–1.8) 0.558

5-10 years 0.89 (0.61–1.3) 0.571 0.82 (0.55–1.2) 0.323 >10 years 0.62 (0.38–1.0) 0.070 0.53 (0.31–0.91) 0.021

Duration of Estrogen use (register)

None 1.00 (reference) 1.00 (reference) <1 years 0.89 (0.52–1.5) 0.670 0.85 (0.49–1.5) 0.572

1-3 years 1.2 (0.71–1.9) 0.539 1.1 (0.66–1.8) 0.728 3-5 years 1.2 (0.65–2.1) 0.583 1.1 (0.59–1.9) 0.797

5-10 years 0.88 (0.49–1.6) 0.675 0.78 (0.42–1.4) 0.425 >10 years 0.29 (0.04-2.1) 0.221 0.26 (0.03-1.8) 0.184

Type of HT use (register-based) None 1.00 (reference) 1.00 (reference)

Any HT use 1.1 (0.85–1.4) 0.488 1.1 (0.83–1.4) 0.588 Estrogen use 0.98 (0.74–1.3) 0.903 0.92 (0.68–1.2) 0.611

Combination therapy use 1.1 (0.85–1.5) 0.406 1.1 (0.87–1.5) 0.325 Self-reported estrogen use 1.0 (0.82–1.3) 0.750 0.99 (0.75–1.3) 0.928

Study 4 (MEDALZ) OR (95% CI) P OR (95% CI) P

Duration of estrogen use None 1.00 (reference) 1.00 (reference)

0-5 years 1.14 (1.10-1.18) <0.001 1.10 (1.06-1.14) <0.001 6-10 years 1.16 (1.12-1.21) <0.001 1.13 (1.10-1.20) <0.001 >10 years 0.94 (0.86-1.02) 0.131 0.91 (0.84-0.99) 0.031

Duration of progesterone use None 1.00 (reference) 1.00 (reference)

0-5 years 1.16 (1.11-1.21) <0.001 1.14 (1.10-1.20) <0.001 6-10 years 1.11 (1.04-1.16) <0.001 1.13 (1.07-1.20) <0.001 >10 years 1.01 (0.87-1.15) 0.959 1.03 (0.90-1.20) 0.611

Duration of combination HT use

None 1.00 (reference) 1.00 (reference) 0-5 years 1.17 (1.12-1.22) <0.001 1.15 (1.11-1.21) <0.001

6-10 years 1.10 (1.04-1.16) <0.001 1.12 (1.06-1.20) <0.001 >10 years 1.01 (0.87-1.18) 0.839 1.05 (0.90-1.22) 0.536

Mode of estrogen use None 1.00 (reference) 1.00 (reference)

Oral 1.13 (1.10-1.17) <0.001 1.10 (1.06-1.14) <0.001 Dermal 1.05 (0.99-1.11) <0.001 1.01 (0.96-1.07) 0.627

Oral and dermal 1.20 (1.13-1.27) 0.215 1.16 (1.10-1.23) <0.001 Mode of progestogen use

None 1.00 (reference) 1.00 (reference) Oral 1.14 (1.10-1.18) <0.001 1.14 (1.10-1.18) <0.001

Dermal 1.07 (0.86-1.34) 0.516 1.06 (0.85-1.33) 0.572 Oral and dermal 1.02 (0.91-1.15) 0.647 1.05 (0.93-1.18) 0.418

51

Duration of estrogen monotherapy

None 1 (reference) 1 (reference) 0-5 yrs 1.13 (1.10-1.17) <0.001 1.10 (1.05-1.13) <0.001

5-10 yrs 1.10 (1.02-1.13) <0.001 1.01 (0.96-1.07) 0.541 >10 yrs 0.89 (0.79-1.01) 0.083 0.83 (0.74-0.95) <0.001

Duration of progestogen monotherapy

None 1 (reference) 1 (reference) 0-3 yrs 1.16 (0.99-1.13) 0.074 1.06 (0.99-1.13) 0.077 >3 yrs 2.45 (1.7-3.47) <0.001 2.40 (1.70-3.40) <0.001

Type of HT None 1.00 (reference) 1.00 (reference)

Any HT 1.01 (0.98-1.10) 0.362 0.99 (0.95-1.01) 0.742 Estrogen HT 1.02 (0.97-1.01) 0.614 0.97 (0.93-1.02) 0.211

Progesterone HT 1.01 (0.94-1.10) 0.691 0.97 (0.90-1.01) 0.496

*In study 2, adjusted for age **In study 1, adjusted for modified Charlson comorbidity index, uterine/ovarian cancer, oophorectomy and hysterectomy **In study 2, adjusted for age, BMI, alcohol, smoking, physical activity, occupation status, number of births, menopause status, any cancer, and surgery ** In study 4, adjusted for socioeconomic status, co-morbidities, surgery, and gynecological cancer

5.4 HT AND COGNITIVE DECLINE

Table 8 shows the risk of cognitive decline among HT users in the CAIDE study. A positive trend was observed in global cognition and episodic memory among women using HT for >5 years at baseline (1998), but this trend was not seen in the follow-up examination (2008), although the point estimate remained the same for global cognition as that observed in 1998. However due to the small number of participants, the confidence interval was wider and included the null value.

52

Tab

le 8

: A

sso

ciat

ion

bet

wee

n H

T u

se a

nd

co

gnit

ive

stat

us

(Stu

dy

3)

*Ad

just

ed f

or

age,

ed

uca

tio

n, A

po

-E s

tatu

s *

*Ad

just

ed f

or

age,

ed

uca

tio

n, h

yste

rect

om

y, A

po

-E s

tatu

s, a

nd

Co

mo

rbid

ity

ind

ex

H

orm

on

e T

he

rap

y u

se

CO

GN

ITIO

N

≤5 y

ear

s >5

ye

ars

Firs

t re

-e

xam

inat

ion

(1

99

8)

Mo

del

1*

β (

95

% C

I)

P

Mo

del

2*

* β

(9

5%

CI)

P

M

od

el 1

* β

(9

5%

CI)

P

M

od

el 2

**

β (

95

% C

I)

P

Glo

bal

co

gnit

ion

0

.04

(-0

.01

-0.1

0)

0.1

6

0.0

4 (

-0.0

2-0

.11

) 0

.20

0

.06

(-0

.00

4-0

.12

) 0

.07

0

.07

(-0

.00

1-0

.13

) 0

.05

5

Mem

ory

0

.60

(-0

.08

-1.3

) 0

.09

0

.07

(-0

.03

-1.4

) 0

.06

1

.0 (

0.3

8-1

.7)

<0.0

1

1.1

(0

.42

-1.9

) <0

.01

Ver

bal

exp

ress

ion

0

.01

(-0

.02

-0.0

4)

0.5

0

0.0

1 (

-0.0

2-0

.04

) 0

.47

0

.01

(-0

.01

-0.0

4)

0.2

2

0.0

1 (

-0.0

1-0

.04

) 0

.35

Psy

cho

mo

tor

spee

d

0.0

1 (

-0.0

1-0

.02

) 0

.24

0

.01

(-0

.01

-0.0

2)

0.4

1

0.0

1 (

-0.0

1-0

.02

) 0

.15

0

.01

(-0

.00

3-0

.02

) 0

.11

Exec

uti

ve f

un

ctio

n

0.0

1 (

-0.0

3-0

.06

) 0

.57

0

.01

(-0

.04

-0.0

5)

0.8

0

0.0

1 (

-0.0

3-0

.06

) 0

.55

0

.01

(-0

.04

-0.0

5)

0.8

2

Seco

nd

re

-e

xam

inat

ion

(2

00

5-2

00

8)

Glo

bal

co

gnit

ion

-0

.01

(-0

.12

-0.0

9)

0.7

6

0.0

4 (

-0.0

7-0

.14

) 0

.48

0

.06

(-0

.03

-0.1

6)

0.2

1

0.0

8 (

-0.0

4-0

.20

) 0

.18

Mem

ory

-0

.00

00

5 (

-0.0

1-0

.01

) 0

.99

0

.00

3 (

-0.0

1-0

.02

) 0

.68

-0

.00

2 (

-0.0

1-0

.01

) 0

.76

-0

.00

6 (

-0.0

2-0

.10

) 0

.48

Ver

bal

exp

ress

ion

-0

.01

(-0

.04

-0.0

2)

0.6

2

-0.0

1 (

-0.0

4-0

.02

) 0

.69

-0

.01

(-0

.04

-0.0

2)

0.5

2

-0.0

1 (

-0.0

4-0

.03

) 0

.81

Psy

cho

mo

tor

spee

d

0.0

01

(-0

.01

-0.0

1)

0.9

7

0.0

02

(-0

.01

-0.0

1)

0.7

2

0.0

06

(-0

.01

-0.0

2)

0.3

9

0.0

04

(-0

.01

-0.0

2)

0.5

8

Exec

uti

ve f

un

ctio

n

-0.0

1 (

-0.0

8-0

.06

) 0

.77

-0

.03

(-0

.10

-0.0

4)

0.3

9

-0.0

5 (

-0.1

2-0

.01

) 0

.14

-0

.04

(-0

.13

-0.0

4)

0.2

8

53

6 DISCUSSION

6.1 OOPHORECTOMY, HYSTERECTOMY, AND RISK OF AD (STUDY 1)

The finding of a protective association between oophorectomy, hysterectomy, and radical hysterectomy against AD is in contrast to previous studies. Surgical removal of ovaries has been studied previously and has been reported to increase the risk of cognitive decline and AD dementia in Mayo Clinic Study of Oophorectomy (Rocca et al., 2007), where an age-at-oophorectomy dependent increased risk of dementia was observed. That finding was replicated in a large Danish register-based cohort study which concluded that hysterectomy, unilateral or bilateral oophorectomy performed before the onset of natural menopause was associated with an increased risk of dementia (Phung et al., 2010). One reason for the difference in results between our study and previous research is the fact that the majority of women (91.8%) in the present study were postmenopausal when they underwent surgery. As far as we are aware, this is the first large register-based study exploring the association between postmenopausal gynecological surgeries with the risk of AD. The major outcome in previous menopause related studies has been cognitive decline not AD (Kok et al., 2006, Farrag et al., 2002). The increased risk of cognitive decline or dementia in relation to induced menopause before the onset of natural menopause is biologically plausible; it could be due to the abrupt loss of secretions of ovarian hormones in contrast to the situation in natural menopause where hormonal senescence develops over years (Farquhar et al., 2005). In our study, removal of ovaries or uterus in already naturally menopausal women did not affect the association between HT and AD. In this study, it was possible to explore the association between oophorectomy, hysterectomy, and radical hysterectomy and probable AD with nationwide coverage. We estimated an 11-15 % reduction in the AD risk among women undergoing gynecological surgery compared to women not undergoing surgery, although absolute risk differences were small. This indicates that postmenopausal gynecological surgery does not increase significantly the woman’s susceptibility to AD. One study in rats observed the same phenomenon, where rats with surgical removal of ovaries after the onset of natural menopause performed better in mnemonic tests than those undergoing induced menopause before the onset of natural menopause; in that experiment, the results were explained as follows; the follicle depleted ovary had led to the development of an androgen rich environment which was detrimental for cognition (Acosta et al., 2009). As women in the present study had also undergone natural menopause before they underwent gynecological surgery, this may be a possible mechanism to explain our results. One of important indications for postmenopausal surgery is an underlying cancer, which itself decreases life span; in this sense it can seem to prevent dementia indirectly through a survival bias effect i.e. some women suffering cancer die before they can develop AD. In the present study, it was possible to ascertain the indication for surgery in our sample, an initially protective association against AD was only observed among women without a history of cancer but the number of women with cancer history was small and thus the failure to detect an association in this group may be due to the study’s lack of power. It is not reasonable to attempt to make a direct comparison of these findings to previous studies because previous experiments focused on how premenopausal induced menopause altered the risk of cognitive decline and dementia. A younger age at induced menopause

54

was related to an increased risk of AD related pathology at postmortem (Bove et al., 2014) and cognitive impairment, and dementia in comparison with women not requiring gynecological surgery (Rocca et al. 2012). It was not possible to control for surgeries taking place in the premenopausal period, and data on important confounders such as ApoE, education, socioeconomic or lifestyle factors, and pre-surgical mental assessment were not available, which might confound the results. However, the availability of information on co-morbidities in the present study is likely to capture some variation in the unmeasured confounders. Data on HT prescriptions, AD diagnosis, and assigning controls to each case was beneficial as Finnish National registers have proved to be rather accurate (Solomon et al., 2014b).

6.2 POSTMENOPAUSAL HT USE AND RISK OF AD AND DEMENTIA (STUDY 1, 2, 4)

6.2.1 Use of HT in relation to oophorectomy and hysterectomy (Study 1) The depletion of ovarian sex steroid hormones after induced menopause has been associated with an increased risk of cognitive decline in older age. In our case-control study on postmenopausal surgeries, we were able to control for HT use. Data on HT use and gynecological surgeries was available since 1995 and 1986 respectively. As the women in our study were almost exclusively postmenopausal, and data on HT prescriptions was available for 7 years later than gynecological surgeries, we could not ascertain the use of HT in pre- and peri-menopausal period. The HT use did not alter the association between surgeries and AD. HT use in the present study was independently related to a lower risk of AD, irrespective of co-morbidities and gynecological surgical status. The use of HT immediately after bilateral oophorectomy and hysterectomy for a short time has been associated with improved cognitive scores (Phillips and Sherwin 1992). In multiple small cross-over trials among surgically-induced and naturally menopausal women, no beneficial effect of HT use has been observed for cognition (Schiff et al., 2005, Wolf et al., 2005), although the use of estrogen alone has been associated with better subjective and objective memory (Moller et al. 2010). Our finding of protective association between long term HT use (10-11 years) towards AD is in line with previous studies where the early use of HT was observed to be more beneficial than late use (Rocca and Henderson 2014). The exact age at the start of HT could not be confirmed in the present study, but the higher risk of AD with a shorter duration and a lower risk with the longest duration of HT point towards a beneficial effect of early start of HT. No specific type of HT was particularly related to AD risk. Our findings are consistent with a previous study where the use of HT for at least 10 years, when started within 5 years of the peri-menopausal period, decreased the risk of cognitive decline (Bove et al., 2014). In view of the fact that all women were postmenopausal in the present study and our finding of an increased risk of AD with a short duration of HT use, the present study favors the critical window theory (i.e. use of HT in late postmenopausal period is not neuroprotective) and also the healthy cell theory where neurons respond to HT when they are healthy, but not when the deterioration has already started; at that time the provision of HT would do more harm than good (Hogervorst 2013). Other possible explanations for protective association between long term use of HT and AD can be the healthy user bias. It is possible that women using HT for a longer duration are healthy at baseline, have healthy life style habits, are better educated or have higher socioeconomic

55

statuses and occupations. As we did not have information on all these variables in the present study, their influence on the observed findings cannot be estimated.

6.2.2 Postmenopausal HT and risk of AD and dementia (Study 2, 4) Overall no significant association was observed between postmenopausal use of HT and AD or dementia in the OSTPRE cohort and the results were similar for any type of HT used. Moreover, the results did not differ whether we used self-reported or register-ascertained HT use and were independent of BMI, physical activity, alcohol intake, smoking, oophorectomy, hysterectomy, education, occupation, menopause status, and co-morbidities in study 2. In the MEDALZ study (study 4), detailed information on the type, as well as dose, and duration of HT use was available through mathematical modelling. An increased risk of AD was observed with any use of systemic estrogen and progestogen, however the use of systemic estrogen HT for >10 years was associated with a lower risk of AD in study 4. Progesterone and combination HT use for >10 years were not significantly associated with altering the risk of AD. Furthermore, a protective association was observed in OSTPRE between long term self-reported HT use and AD; this can be explained by the fact that self-reported documentation of HT use dated from 1989, whereas data on register-based HT use for the same women was available only from 1995. Another explanation can be reverse causation which means that AD (or more precisely, its preclinical symptoms) affected the exposure to HT (or self-reporting of HT), or it is simply a chance finding. This finding agrees with the Cache county study where a reduced risk of AD was detected among women using HT for more than 10 years (Shao et al., 2012). One observational study reported that early initiation of HT around menopause was protective against AD (Bagger et al., 2005). Similarly in one study, the use of HT in youngest age tertiles decreased the AD risk more than in women in the oldest age range (Henderson et al., 2005). Prior use of HT was protective against AD in a cohort study only when HT use exceeded 10 years (Zandi et al., 2002a). Increased levels of endogenous estrogens have also been related to a lower risk of AD and less cognitive decline in cohort studies (Fox et al., 2013, Rasgon et al., 2005). In a case-control study, the use of HT protected against AD independent of education and age at menopause (Waring et al. 1999). The increased risk of AD among short term HT users observed in study 4 relates to start of HT in the late postmenopausal period, as the average ages at the start of HT in this study for cases and controls were 64.1 and 63.8 years respectively. This is in accordance with the findings from the WHIMS, the largest clinical trial to date examining the relationship between the use of HT and all cause dementia. WHIMS explored the risk of all cause dementia as a secondary outcome with use of both opposed (CEE+MPA) and unopposed (CEE only) HT versus placebo among women >65 years old. The use of opposed HT increased the dementia risk, but this did not occur with unopposed HT (Shumaker et al., 2003b, Shumaker et al., 2004b). Findings from OSTPRE about the protective association between long term HT use and AD can be attributable to the fact that the women in our cohort were around 10 years younger (average age at baseline 54.1 for AD cases and 52 years for women without AD) than women in the WHIMS trial, and the main outcome in our study was AD whereas it was all cause dementia in WHIMS. In the WHIMS trial, women were randomized to receive opposed therapy as CEE combined with MPA, while in OSTPRE study, the women with an intact uterus mainly received estradiol combined with norethisterone or levonorgesterel (but not MPA). Moreover, Finnish women who have undergone a hysterectomy receive mainly estradiol on its own

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(Pentti et al., 2006). The difference between these two studies may be attributable to the differences in the effects exerted by these different estrogen preparations. The lack of an overall significant association between any HT use and AD in study 2 is consistent with previous studies where HT use was not associated with AD, and self-reported long term HT use did not reduce risk of dementia among >70 years old women (Petitti et al., 2008, Kang et al., 2004b).

6.3 USE OF HT AND COGNITIVE DECLINE (STUDY 3)

This study was able to test the association of cognitive status with HT use in the CAIDE longitudinal study. Overall, no strong evidence for protective effect of HT use on cognitive decline was observed. However, our findings point to a selective beneficial effect of HT on cognitive domains. In 1998, women using HT for >5 years performed better in global cognition and episodic memory tests than women taking these preparations <5 years. These findings are consistent with the Women’s Health Initiative Study for Cognitive Aging, where a differential beneficial effect of HT was observed in different cognitive domains (Espeland et al. 2013b). The average age at baseline for HT users and non-users was 70.8 and 68.8 years respectively, which indicates that administration of HT commenced in both groups in the postmenopausal period. The protective effect for global cognition and episodic memory among >5 years HT users indicates that the use of HT might have started in the early postmenopausal period. No significant difference was observed for APOE-Ɛ4 carrier status among HT users and non-users; the results were the same after controlling for education, APOE, and hysterectomy status. There was no information available about menopause status at baseline, age at the start of HT, type and time of initiation of HT with respect to menopause. For these reasons in this study, it was necessary to extrapolate the start of HT in early or late postmenopause by considering age at baseline (1998). The validity of the present study was increased by the long follow-up time (8 years) in a population based cohort and the use of established psychological tests to assess cognitive status as well as having detailed information available on education, APOE status and various co-morbidities. Previous observational studies investigating the association between postmenopausal HT use and the risk of cognitive decline have revealed inconsistent findings. The results emerging from the present study are in line with a cohort study where former use of HT was protective against AD compared to current use; that study examined 1889 women with a mean age of 74.5 years after controlling for age, education, and APOE status (Zandi et al., 2002a). Similarly, the lifetime use of HT was associated with improved global cognition among >65 years old women (Carlson et al., 2001). A prolongation in length of lifetime exposure to HT decreased the risk of cognitive impairment and was protective against AD (Rasgon et al., 2005, Fox et al., 2013). In two small cross-sectional studies, the use of HT was associated with improved performance on verbal memory (Wharton et al., 2009b, Maki et al., 2011). In a pilot study, early initiation of HT use was selectively beneficial for some cognitive domains but this benefit was not achieved with late HT use (MacLennan et al., 2006).

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6.4 METHODOLOGICAL CONSIDERATIONS

The association between HT use and late-life dementia and cognitive status is complex and confounded by multiple psychological, medical, and behavioral variables in a woman’s life which act as predictors of HT use including race, financial status, education, obesity, diabetes mellitus, intake of supplements, and overall health status (Gleason et al. 2012). In other words, where one theory revolves around the time of initiation of HT, the other proposes that it might be the health status of the user rather than simply her age which explains the effects of HT on brain functions (Hogervorst 2013). The observational studies in this thesis consist of two case control studies and two cohort studies. The greatest strengths in the present thesis are that almost all studies had a large sample size and long follow-up times. However, our follow-up time was still not long enough to investigate the association between premenopausal use of HT with AD. Similarly, we could not explore the association between induced menopause commencing before the onset of natural menopause with AD. This is due to the fact that in all four studies of the present thesis, the women were mainly postmenopausal. The use of HT in three studies was ascertained from the Finnish national prescription register (study 1, 2, and 4), which is maintained by the Social Insurance Institution of Finland. Nationwide data on prescriptions has been collected by the Social Insurance Institution since 1995 with almost universal coverage (97% of all prescribed medicines). Duration of medication (HT) use is calculated based on prescription purchase data. ATC codes for each purchase history are processed for each individual. Purchase history is used to calculate defined daily dose which is then used to determine the exposure period for each drug. The prescription register does not cover drugs used in public nursing homes or during stay in hospitals (Tolppanen et al. 2016). This may introduce a serious limitation to our studies, where AD is the main outcome (study 1, 2, and 4) since in Finland around 30% of persons with AD live in nursing homes or are institutionalized. However, this is unlikely to have affected the results in studies 1 and 4 because these studies included only those women who were community-dwelling at baseline. In addition, exclusion of exposure data 0-5 years before the outcome did not impact on the results and conclusions in these studies. Study 2 was also restricted to women who were community-dwelling and free of AD and dementia at baseline. An important point to consider about register-based HT use is that register-based data would misclassify those who discontinued HT use before 1995 as nonusers. It is unlikely that this misclassification was differential in those who later developed AD and those who did not. Therefore it would lead to an underestimation (i.e. wider confidence intervals) of the association between HT use and AD with the register-based data (study 2). The AD diagnosis in studies 1, 2, and 4 was obtained from the Finnish special reimbursement register, which has been determined previously to possess high validity and predictive value for AD diagnosis, thus eliminating the possibility of misclassification of AD (Solomon et al., 2014b). Diagnosis of probable AD in Finland is based on the DSM-IV criteria for AD and NINCS-ADRDA criteria and supported by abnormal MRI and/or CSF findings typical for AD (McKhann et al., 1984, American Psychiatric Association 1994). The Finnish Current Care Guideline recommends that all persons with AD are treated with anti-dementia drugs unless there is a specific contraindication (such as gastric ulcer/intestinal tract operation <6 months ago or severe asthma or chronic obstructive pulmonary disease which are contra-indications for acetylcholinesterase inhibitors). Though the special reimbursement register has high positive predictive value for AD diagnosis, we cannot rule

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out the false negatives, because it may be that some women with AD did not receive a special reimbursement. This group of women can contaminate the control group. Though it would dilute our findings towards null, it is a point worth considering. For study 2, AD diagnosis was taken from the special reimbursement register from 1999-2009. We could not ascertain the AD diagnosis prevailing among our study population from 1989-1999, as the special reimbursement register for AD was only established in 1999 when acetylcholinesterase inhibitors became available in Finland. It is possible that women who had deceased before 1999, had preclinical AD or AD. However, the number of these women was small (n=619) and thus it is not likely to have exerted any major impact on the results. Data on oophorectomy, hysterectomy, and radical hysterectomy and malignancy of cervix uteri, corpus uteri, uterus or ovary (ICD-10 codes C53-C56 and C57.0 and corresponding ICD-9 and ICD-8 codes) for study 1, and 4, was collected from the National Hospital Discharge Register. Registration of hospitalizations and prescriptions is mandated by law in Finland, but currently there are no validation studies on oophorectomy and hysterectomy codes in the hospital discharge register. One major limitation in our studies is lack of ascertainment for the start of HT in relation to the onset of menopause as women were mainly postmenopausal in all studies. Self-reported use of HT in study 2 and 3 is subject to a recall bias, though this was unlikely considering the previous validation study conducted in the same cohort where a postal inquiry was shown to be a reliable method of recording long-term HT use in Finnish postmenopausal women [Sandini et al., 2008]. Moreover, self-reported use of HT was balanced in study 2 by validation of HT from registers for a slightly shorter duration of time than self-reported use. The similar results obtained with both modes of data collection added reliability to the self-reported results. Another bias to be considered in cohort studies (study 2 and 3) is the selection bias and healthy user bias. We cannot rule out that women responding to postal questionnaires in study 2 and self-reported HT use in study 3 were more educated, with a healthy life style, and were more socially active than women not responding to these questionnaires. Though register based studies effectively account for drugs dispensed at pharmacies, they cannot evaluate the actual use of those medicines at the individual level. A common limitation of observational studies is the non-random allocation of exposure, meaning that differences between HT users and nonusers may partially explain our findings. As is common with register-based studies, we could not account for important factors affecting the HT-AD association either acting as a confounder or an effect modifier in study 1 and 4. These kinds of confounders include APOE status, blood pressure, cholesterol levels, lifestyle habits such as smoking, alcohol, physical activity, details on socioeconomic status, social activity, marital status, number of deliveries, and diabetes mellitus etc, which affect the overall health status of a person and either promoting or impairing cognitive and brain reserve thus acting as a barrier or a shortcut to the onset of debilitating illness like AD. We were able to account for certain comorbidities in two studies (1 and 4) which might take into account these potential confounders to some extent, such as the presence of cardiovascular diseases and cancer. In addition, the findings from study 2, where we had detailed information on lifestyle factors and socioeconomic position and education, were comparable to those from study 4. In study 3 that assessed the association between HT and cognitive decline, we were also able to account for APOE; this genetic factor did not have any effect on the results of that study. In summary, similar results were obtained in all of the studies making up this thesis, i.e longer HT exposure was associated with better cognitive outcomes. We interpret this to mean that the association of longer duration of HT and lower risk of AD was not due chance alone, but it cannot rule out the possibility that it could be explained by bias or confounding. Although we were able to adjust for multiple

59

lifestyle- and socioeconomic position- related confounders in studies 2 and 3, it could be that these confounders do not adequately capture the confounder that they hope to measure, or that there is some unmeasured confounder.

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7 CONCLUSIONS

Based on the findings from the four studies included in this thesis, the following conclusions

can be drawn

1. Postmenopausal gynecological surgery i.e. oophorectomy, hysterectomy, and

hysterectomy with bilateral oophorectomy, was not a significant predictor of AD,

irrespective of indication of surgery or HT use.

2. Postmenopausal HT was not significantly associated with AD and dementia in a

longitudinal prospective cohort study while controlling for various midlife lifestyle

and socioeconomic factors.

3. Long term postmenopausal HT (10-11 years) was associated with a lower risk of AD

independent of oophorectomy and hysterectomy status.

4. Postmenopausal HT was not significantly related to cognitive decline although a

protective association was detected between long term HT use and global cognition

and episodic memory.

5. Short term postmenopausal HT use among women aged >65 years was associated

with an increased risk of AD.

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8 FUTURE PERSPECTIVES

Current findings from clinical trials and observational studies on the association between HT use and the risk of cognitive decline, dementia, and AD have investigated previously putative lifestyle, socioeconomic, and genetic factors affecting this association. The type of HT, its dose, duration, and formulation along with time of initiation with respect to the onset of natural menopause or induced menopause, and health status at baseline are among those factors which influence the onset of dementia, cognitive decline, and AD. Recent clinical trials such as KEEPS and ELITE (Early versus Late Intervention Trial with Estradiol) have provided additional information about HT use and cognitive decline. ELITE explored the risk of cognitive decline in the context of the serum hormone levels among women within 6 and 10 years of their menopause. The endogenous estrogen level was not associated with verbal memory in either group, while sex hormone binding globulin and progesterone were positively associated with verbal memory in the early group only (Henderson et al., 2013). Moreover, in a recent study from the ELITE trial, the use of estradiol when initiated within 6 years of menopause did not affect cognitive status differently than initiation of >10 years after menopause. HT use was neither beneficial nor harmful to cognition at these two time points (Henderson et al., 2016). Similarly findings from the KEEP-cog trial concluded that menopausal hormone therapy was neither beneficial nor harmful for cognition, while low dose oral-CEE but not transdermal estradiol, improved symptoms of anxiety and depression (Gleason et al., 2015). Therefore, these findings do not support the concept of use of HT within a certain time window that is around menopause as was suggested from the results originating from WHIMS. However, findings from KEEPS-cog are not generalizable to women using HT for >4 years and, but importantly, in neither trial (KEEPS-cog and ELITE), was menopausal hormone therapy found to be harmful in young women. A recent development in the use of HT has been based on research supporting the critical time period, low dose estrogen is recommended to alleviate menopausal symptoms but only for a short duration of time (Scott et al., 2014). Moreover, according to a recent Cochrane reviews, fractures are the only outcome for which there is strong evidence of benefits from HT use, whereas there are little or no benefits of HT on cardiovascular diseases, and there may be a higher risk of adverse events such as stroke, dementia, and venous thromboembolic events (Marjoribanks et al., 2012, Boardman et al., 2015). However, the current consensus statement on menopausal hormone therapy recommends initiation of HT before age 60 or within 10 years after menopause, but does not provide any guidelines on its discontinuation (de Villiers et al., 2016). Considering the systemic complications of oral HT use despite its neuroprotective potential, the focus has been to develop SERM drugs which would have tissue specific effects, for example, the drug would have neuroprotective effects through binding to estrogen receptors in brain only, while sparing peripherally located estrogen receptors in uterus and breast etc. to avoid HT-related peripheral deleterious effects (Barron, Pike 2012). The currently available SERMs act as estrogen antagonists in brain and thus do not exert the neuroprotective effects of estrogen (Komm and Mirkin 2003). A new approach in this context is the tissue selective estrogen complex (TSEC). TSEC refers to a combination of SERM with one or more estrogens, which aims to combine the agonistic activity of estrogens on estrogen receptors along with the tissue selectivity of SERMs (Komm and Mirkin 2013).

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Both TSEC and SERM can be used without progesterone even in women with an intact uterus, which is a promising approach as it can avoid progesterone related side effects (Santen et al. 2014). Molecular and pharmacological effects of estrogens, SERMs and TSEC differ from each other. Recently TSEC has been claimed to be a promising therapy where the neuroprotective effect of estrogen is combined with SERMs to prevent the peripheral harmful effects of estrogens (Komm and Mirkin 2013). Another recent concept in the HT and dementia relationship is to compare the effect of short-term HT use (2-3 years) among recently menopausal women which is then stopped versus those who use HT for a longer duration. In one study, this former approach was associated with a 66% relative reduction in the risk of cognitive decline independent of age, alcohol use, smoking, and education. This finding suggests that there might be long term beneficial effects linked with the short term HT use around menopause (Bagger et al., 2005). The reasons for the inconsistent findings from clinical trials and observational studies need to be clarified; why on one side do observational studies usually favor the use of HT to protect against dementia and cognitive decline, but these positive results cannot be duplicated in clinical trials? Based on results from this thesis and the literature review, it is tempting to consider estrogen as a neuroprotective hormone, yet its clinical impact seems to be double-edged – in some cases it is beneficial – in others, it is detrimental. Considering recent advances and the exploration of the critical time period for HT use theory in the KEEPS-cog and ELITE trials, the next step might be to re-examine the population from KEEPS-cog once the participants reach the age of onset of dementia. Since the KEEPS-cog trial examined the association of 4 years of HT use around menopause with cognition, it could be an excellent source to examine the long-term effects of short-term HT use around menopause on cognitive decline and dementia, as suggested by one previous study [Bagger et al., 2005]. Similarly, clinical trials with tissue (especially brain) specific estrogen receptor modulators might add more pieces to the AD-HT jigsaw puzzle.

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ISBN 978-952-61-2402-5ISSN 1798-5706



BUSHRA IMTIAZ

HORMONE THERAPY AND THE RISK OF DEMENTIA, COGNITIVE DECLINE AND ALZHEIMER’S DISEASE

Depletion of estrogen and progesterone at menopause may predispose to cognitive decline and Alzheimer’s disease (AD).

Hormone therapy (HT) has been suggested to prevent or delay this. The findings from

previous studies have been inconsistent. AD-HT association is a complex scenario and is subjected to various genetic and lifestyle factors. This thesis explored the direction of

association between HT, AD, and cognition in two nation-wide case-control studies and two

longitudinal cohort studies.

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