Clinical, cognitive and genetic Clinical, cognitive and genetic predictors of conversion from predictors of conversion from

amnestic mild cognitive impairment to amnestic mild cognitive impairment to Alzheimer’s disease in Chinese older Alzheimer’s disease in Chinese older

adultsadults Prof. Leung-Wing ChuProf. Leung-Wing Chu

MD, FRCP MD, FRCP (Edin. & Glas.)(Edin. & Glas.), FHKCP, FHKAM, FHKCP, FHKAM (Medicine) (Medicine)

Honorary Clinical Professor, and Honorary Clinical Professor, and

Associate Director, Centre on Ageing, andAssociate Director, Centre on Ageing, andChairman, HKU AD Research Network, SRT Healthy Chairman, HKU AD Research Network, SRT Healthy

Ageing,Ageing,The University of Hong KongThe University of Hong Kong

Chief, Division of Geriatrics, Queen Mary HospitalChief, Division of Geriatrics, Queen Mary Hospital

(Chu LW, Mok W, Chung CP, Chan M, Yik PY, Kwan F, Chan CSY , Song YQ, Lee P)

**OC126March 29, 2011

Conflict of InterestConflict of Interest

All authorsAll authors– Chu LW, Mok W, Chung CP, Chan M, Chu LW, Mok W, Chung CP, Chan M,

Yik PY, Kwan F, Chan CSY , Song YQ, Yik PY, Kwan F, Chan CSY , Song YQ, Lee PLee P

Has no real or apparent conflicts Has no real or apparent conflicts of interest to reportof interest to report

**ADI2011-1083OC126

Prevalence of AD in Chinese (Systematic analysis of 1980-2004 25 studies in

China*)

*Dong et al, 2007*Dong et al, 2007

0.30.4 0.30.5 0.91.82.3

4.4 3.8

11 10.6

23.421.1

31.8

05

101520253035

60-64 65-69 70 -74

75 -79

80 -84

85 -89

90+

Age (years)

M

F

LowerPrevalence InMen%

Prevalence of Very Mild & Prevalence of Very Mild & Mild Dementia in Hong Kong Mild Dementia in Hong Kong Older people 60+Older people 60+ Prevalence of dementia =11.4%Prevalence of dementia =11.4%

Very mild (CDR 0.5) = 5.8%Very mild (CDR 0.5) = 5.8% Mild (CDR 1.0) = 5.4Mild (CDR 1.0) = 5.4

Subtypes Subtypes – 73.5% possible AD73.5% possible AD– 22.4% possible VaD22.4% possible VaD– 3.9% PD dementia or LBD3.9% PD dementia or LBD

(Lam L et al, 2008)(Lam L et al, 2008)

Delay in Diagnosis in ADDelay in Diagnosis in ADSymptom onset and 1st consultation Symptom onset and 1st consultation

Mean Delay -- 3.1 years Mean Delay -- 3.1 years in AD patientsin AD patients11

Symptoms ignored as Symptoms ignored as ““normal ageing!normal ageing!””

11Chiu KC et al, 2002Chiu KC et al, 2002•(More than 2 times that of Caucasian AD patients (i.e. 1.2 years in Caucasian

dementia patients2 ). 2Cattel C et al, J Gerontol: Med Sci 2000; M98)

Undiagnosed Dementia Undiagnosed Dementia in the HK Communityin the HK Community Prevalence of previously Prevalence of previously

diagnosed dementiadiagnosed dementia– 1.7% (including old age homes)1.7% (including old age homes)11

– 0.33%0.33% (excluding old age homes) (excluding old age homes) 22

Undiagnosed dementia: Estimated Undiagnosed dementia: Estimated prevalence – 9.7% to 11.1%prevalence – 9.7% to 11.1%

11Chu LW et al, 1998; Chu LW et al, 1998; 22Chu LW et al, 2005Chu LW et al, 2005

Mild cognitive impairment (MCI) is a clinical Mild cognitive impairment (MCI) is a clinical syndrome defined assyndrome defined as– cognitive decline greater than that expected cognitive decline greater than that expected

for a person’s age and education level for a person’s age and education level – but does not affect notably with activities of but does not affect notably with activities of

daily life (Gauthier S et al, Lancet 2006)daily life (Gauthier S et al, Lancet 2006) MCI refers to MCI refers to

– a transitional cognitive phase between a transitional cognitive phase between cognition of normal aging and mild dementia & cognition of normal aging and mild dementia &

– may precede the onset of dementia or AD may precede the onset of dementia or AD (Petersen et al, 1999 & 2001)(Petersen et al, 1999 & 2001)

Mild cognitive Mild cognitive Impairment (MCI) Impairment (MCI)

MCI SubtypesMCI Subtypes Amnestic MCI (aMCI)Amnestic MCI (aMCI)1. MCI (Amnestic)1. MCI (Amnestic) (Single memory domain) (Single memory domain) AlzheimerAlzheimer’’s disease (AD)s disease (AD)

2. MCI (Multiple domains slightly impaired)2. MCI (Multiple domains slightly impaired) AlzheimerAlzheimer’’s disease; Vascular Dementias disease; Vascular Dementia

Non-amnestic MCI (naMCI)Non-amnestic MCI (naMCI)3. MCI (Single Non-memory Domain)3. MCI (Single Non-memory Domain) Fronto temporal Dementia; Lewy Body Fronto temporal Dementia; Lewy Body

Dementia; Vascular Dementia; Primary Dementia; Vascular Dementia; Primary Progressive Aphasia; ParkinsonProgressive Aphasia; Parkinson’’s Disease; s Disease; Alzheimer's DiseaseAlzheimer's Disease

Progression of MCI Progression of MCI Conversion rate and Conversion rate and PredictorsPredictors Progression of aMCI to dementia 12% Progression of aMCI to dementia 12%

per year; 80%/6 years (Petersen, 1999 per year; 80%/6 years (Petersen, 1999 & 2001)& 2001)

Clinical, neuropsychological, genetic Clinical, neuropsychological, genetic predictors of conversion or progression predictors of conversion or progression to dementia / ADto dementia / AD– Neuropsych. Tests, particularly delayed Neuropsych. Tests, particularly delayed

recall memory test, APOE4 recall memory test, APOE4 (Petersen (Petersen 1999, Fleisher 2006)1999, Fleisher 2006)

Other predictors: Imaging (MRI, PET), csf biomarkers

Predictors of amnestic Mild Predictors of amnestic Mild Cognitive Impairment Cognitive Impairment (aMCI) conversion to (aMCI) conversion to dementiadementia

Clinical predictor: Body Mass Index (BMI) as a Clinical predictor: Body Mass Index (BMI) as a predictor has not been studied fullypredictor has not been studied fully

Non-demented older adults –low BMI predicts Non-demented older adults –low BMI predicts dementia/AD in several studiesdementia/AD in several studies

MCI: Low BMI MCI: Low BMI more cognitive decline but not more cognitive decline but not dementia conversion in 1 study (Cronk et al, 2010)dementia conversion in 1 study (Cronk et al, 2010)

Limited Chinese data on MCI onLimited Chinese data on MCI on– The clinical, genetic & cognitive predictors of The clinical, genetic & cognitive predictors of

conversion of MCI to dementia,conversion of MCI to dementia,– Wang et al, 58 MCI subjects 32.7% Wang et al, 58 MCI subjects 32.7% AD over 3 AD over 3

yearsyears Only cognitive performance independent predictor (APOE & Only cognitive performance independent predictor (APOE &

hippocampal volume – NS)hippocampal volume – NS)

Objectives of the studyObjectives of the study

To investigate the To investigate the conversion rate of conversion rate of aMCI to AD/dementia in aMCI aMCI to AD/dementia in aMCI in Chinese in Chinese older adults (Southern Chinese)older adults (Southern Chinese)

To investigate the clinical, genetic & To investigate the clinical, genetic & cognitive predictors of conversion from cognitive predictors of conversion from amnestic mild cognitive impairment amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) (aMCI) to Alzheimer’s disease (AD) – Particularly, to study if BMI predicts Particularly, to study if BMI predicts

conversion of aMCI to AD*conversion of aMCI to AD*in Chinese older adults (Southern Chinese)in Chinese older adults (Southern Chinese)*In our previous cross-sectional study, AD & aMCI lower BMI than

cognitively normal older adults

MethodsMethods Design:Design: A one-year cohort studyA one-year cohort study Setting:Setting: Ambulatory setting Ambulatory setting Subjects:Subjects: Chinese older adults, aged 55 to 93 Chinese older adults, aged 55 to 93

years old, with aMCI criteria modified from years old, with aMCI criteria modified from the Petersen’s criteria. the Petersen’s criteria.

Measurements:Measurements: – Baseline demographic, Baseline demographic, – BMI, BMI, – co-morbid diseases, co-morbid diseases, – cognitive including MMSE, ADAS-cog cognitive including MMSE, ADAS-cog – neuropsychological tests, and neuropsychological tests, and – apolipoprotein E genotype (APOE) apolipoprotein E genotype (APOE)

aMCI criteria- Modified from Petersen et al (1999) the presence of memory

complaint (corroborated by an informant),

impaired memory function for age and education (< 1SD verbal memory recall test)*

intact activities of daily living and no dementia (by DSM-IV criteria) *Note: 1SD better Sens. & spec. than 1.5 SD in predicting dementia (Busse A et

al, 2006)(delayed word recall score < 1 SD below normal age-and education-matched

mean for Chinese older adults)

MethodsMethods Follow-up: Follow-up: All subjects were followed All subjects were followed

up for one year. up for one year. Outcome: Outcome:

– Dementia by DSM-IV criteria & Dementia by DSM-IV criteria & – AD was diagnosed by the NINCDS-AD was diagnosed by the NINCDS-

ADRDA criteria for ADRDA criteria for probable ADprobable AD

ResultsResults

243 Chinese older adults with 243 Chinese older adults with aMCI were recruited from Jan. aMCI were recruited from Jan. 2001 to Nov. 20092001 to Nov. 2009

One year follow-up, 16.5% One year follow-up, 16.5% (n=40) developed dementia (n=40) developed dementia (by (by DSM-IV criteria)DSM-IV criteria)* * – All having Alzheimer’s disease (by All having Alzheimer’s disease (by

NINCDS-ADRDA criteria)NINCDS-ADRDA criteria)*versus 0.5% (2 out of 444) in another cohort of cognitively normal Chinese older adults in HK

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI conversion to ADconversion to AD Bivariate analyses showed that Bivariate analyses showed that

– advanced age, low body mass index advanced age, low body mass index (BMI), APOE4+ (1 or 2 copies), low (BMI), APOE4+ (1 or 2 copies), low MMSE, DWRT, ADAS-cog and MMSE, DWRT, ADAS-cog and neuropsychological assessment neuropsychological assessment tests’ scores increased the risk of tests’ scores increased the risk of conversion to AD significantlyconversion to AD significantly

– Arthritis & CHD showed only non-Arthritis & CHD showed only non-significant trends significant trends

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI conversion to ADconversion to AD(Demographic, co-morbid ds.) (Demographic, co-morbid ds.) Predictor Predictor at baselineat baseline

Convert to Convert to ADAD

(n = 40)

Stable Stable (n = 203)

p

Sex (F),%) Sex (F),%) 60.0 60.0 72.472.4 0.116 0.116 Age, yrs. Age, yrs. 77.38 ± 5.61 77.38 ± 5.61 74.90 ± 74.90 ±

6.44 6.44 0.0240.024

Education Education level, yrslevel, yrs

3.10 ± 4.06 3.10 ± 4.06 2.83 ± 7.05 2.83 ± 7.05 0.695 0.695

BMI, Kg/m2 BMI, Kg/m2 22.26 ± 3.18 22.26 ± 3.18 24.23 ± 24.23 ± 3.57 3.57

0.0010.001

Arthritis Arthritis 7.5 7.5 20.3 20.3 0.055 0.055 CHD CHD 20.0 20.0 10.4 10.4 0.087 0.087 Note: Mean ± SD, or %; CHD=coro heart

ds

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI conversion to ADconversion to AD (Co-morbid ds., genetic) (Co-morbid ds., genetic) PredictorPredictorat baselineat baseline

Convert to Convert to ADAD

(n = 40)

Stable Stable (n = 203)

p

HT HT 55.055.0 58.4 58.4 0.689 0.689 DM DM 22.5 22.5 26.7 26.7 0.5770.577Depression Depression (treated)(treated)

5.05.0 5.05.0 0.9890.989

HyperlipidemHyperlipidemiaia

70.070.0 62.4 62.4 0.3600.360

APOE4+ APOE4+ (versus 4-)(versus 4-)

35.0 35.0 15.5 15.5 0.0040.004 Note: %

Bivariate analyses of Bivariate analyses of predictors of aMCI predictors of aMCI conversion to ADconversion to AD(Cognitive, neuropsychological tests) (Cognitive, neuropsychological tests)

PredictorPredictorat baseline (at baseline (Mean ± Mean ± SD)SD)

Convert to Convert to ADAD

(n = 40)

Stable Stable (n = 203)

p

MMSE MMSE 21.90 ± 4.04 21.90 ± 4.04 23.52 ± 23.52 ± 3.59 3.59

0.0110.011

ADAS-cog ADAS-cog 16.52 ± 5.47 16.52 ± 5.47 14.49 ± 14.49 ± 5.52 5.52

0.0350.035

DWRT,10-word DWRT,10-word 1.10 ± 1.08 1.10 ± 1.08 2.33 ± 1.70 2.33 ± 1.70 <0.00<0.001 1

Selective Reminding Selective Reminding Test Test 30-min recall 30-min recall

0.60 ± 1.43 0.60 ± 1.43 2.51 ± 2.62 2.51 ± 2.62 <0.00<0.0011

Visual reproduction-Visual reproduction-delayed recalldelayed recall

1.23 ± 2.46 1.23 ± 2.46 6.47 ± 7.53 6.47 ± 7.53 <0.00<0.001 1

(Most cognitive, neuropsychological tests p<0.05)(Most cognitive, neuropsychological tests p<0.05)

Logistic regression Logistic regression analyses: Independent analyses: Independent predictors of aMCI predictors of aMCI conversion to ADconversion to AD

PredictorPredictor Relative Relative Risk (RR)Risk (RR)

95% CI RR 95% CI RR p

APOE4+ APOE4+ (vs. (vs. 4-)4-)

2.702.70 1.13 – 6.481.13 – 6.48 0.0260.026

BMI, BMI, Kg/m2Kg/m2 0.840.84 0.75 – 0.950.75 – 0.95 0.0040.004SRT-30SRT-30 0.750.75 0.58 – 0.970.58 – 0.97 0.0270.027VR-Delayed VR-Delayed RecallRecall

0.790.79 0.67 – 0.930.67 – 0.93 0.0040.004

Logistic regression Logistic regression analyses: Independent analyses: Independent predictors of aMCI predictors of aMCI conversion to ADconversion to AD After adjustment for confounders, logistic After adjustment for confounders, logistic

regression analyses showed that regression analyses showed that – APOE4+ (vs. 4-) (RR=2.70),APOE4+ (vs. 4-) (RR=2.70),– BMI (RR=0.84), BMI (RR=0.84), – Verbal memory test: 30-minute recall of the selective Verbal memory test: 30-minute recall of the selective

reminding test (RR=0.75) reminding test (RR=0.75) – Visual memory test: delayed recall score in visual Visual memory test: delayed recall score in visual

reproduction test (RR=0.79), and reproduction test (RR=0.79), and

werewere significant independent predictors for conversion significant independent predictors for conversion to AD. to AD.

Age, arthritis, CHD were non-significant & Age, arthritis, CHD were non-significant & MMSE, DWRT, ADAS-cog were not independent MMSE, DWRT, ADAS-cog were not independent

predictors because of SRT-30 & VR-delayed wpredictors because of SRT-30 & VR-delayed w

DiscussionDiscussion

Similar to previous studies, we found Similar to previous studies, we found – APOE4, low cognitive / neurpsych memory test APOE4, low cognitive / neurpsych memory test

predicts conversion of aMCI to dementia/AD in predicts conversion of aMCI to dementia/AD in (Southern) Chinese older adults (with aMCI )(Southern) Chinese older adults (with aMCI )

However, to our knowledge, this is the 1However, to our knowledge, this is the 1stst study study – BMI predicts future risk of aMCI to BMI predicts future risk of aMCI to

dementia/AD dementia/AD Low BMI increases the riskLow BMI increases the risk One kg/m2 less in BMI increases the risk of aMCI to One kg/m2 less in BMI increases the risk of aMCI to

dementia (AD) by 16%dementia (AD) by 16%

DiscussionDiscussion In our previous cross-In our previous cross-

sectional study on 3 sectional study on 3 groups of older adultsgroups of older adults– Significant progressive Significant progressive

decline in BMI decline in BMI reported from reported from NNaMCIaMCIADAD(Chu LW et al JAD, 2009) (Chu LW et al JAD, 2009)

Low BMI can either be a Low BMI can either be a risk factor or preclinical risk factor or preclinical symptom/sign of aMCI symptom/sign of aMCI conversion to ADconversion to AD

Cognitively normal

24.6 ± 4.2 Kg/m2

aMCI 23.9 ± 3.6 Kg/m2

AD 22.9 ± 3.7 Kg/m2

ConclusionsConclusions

In Chinese older adults, In Chinese older adults, – low BMI, as well as low BMI, as well as – the presence of apolipoprotein epsilon 4, and the presence of apolipoprotein epsilon 4, and – poor performance in delayed recall tests in poor performance in delayed recall tests in

verbal and visual memory tests verbal and visual memory tests predict increased risks of aMCI predict increased risks of aMCI conversion to AD in this 1-year conversion to AD in this 1-year cohort study.cohort study.

Future studies needed.Future studies needed.

AcknowledgementAcknowledgement

Co-investigators: Co-investigators: Mok W, Chung CP, Chan M, Song YQ, Lee P

Research staff:Research staff:– Yik PY, Kwan F, Chan CSY

Research grant support:Research grant support:– SK Yee Medical Foundation, Hong KongSK Yee Medical Foundation, Hong Kong– SRT Healthy Aging, the University of Hong SRT Healthy Aging, the University of Hong

Kong: Kong: Alzheimer’s Disease Research NetworkAlzheimer’s Disease Research Network

Thank Thank youyou