the genetics education project the genetics of alzheimer disease wendy s meschino md frcpc fccmg...
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The Genetics Education ProjectThe Genetics Education Project
The Genetics of Alzheimer Disease
Wendy S Meschino MD FRCPC FCCMG Clinical Geneticist, North York General Hospital Assistant Professor, Department of Paediatrics
University of Toronto
June C Carroll MD CCFP FCFP Sydney G. Frankfort Chair in Family Medicine
Associate Professor, Department of Family & Community Medicine Mount Sinai Hospital, University of Toronto
Funded by: Ontario Alzheimer Strategy Physician Education Initiative Ontario Women’s Health Council
Version: February 2006
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Acknowledgements:Mary Jane Esplen PhD RNNCIC Scientist & Associate Professor
Department of Psychiatry, University of TorontoToronto General Research Institute, UHN
Peter St George-Hyslop MD FRCPCDirector, Centre for Research in Neurodegenerative Diseases
Professor, Department of Medicine, University of Toronto
Andrea L Rideout MS CGC CCGCCertified Genetic Counsellor
Project Manager – The Genetics Education Project
Funded by: The Ontario Women's Health Council as part of its funding to The Genetics Education Project
* Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.
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Objectives
To review genetic aspects of Alzheimer Disease– risk assessment– genes associated with familial AD– genetic counselling– genetic testing
To assist health care providers in discussing the benefits, risks & limitations of genetic services
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What’s so different about genetic testing for adult-onset diseases like AD?
Predictive– will the condition develop?– when?– how severe?– will interventions make a difference?
Direct implications for family members Ethical, legal and social issues
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Why should health care professionals know about genetic testing for adult-onset
hereditary diseases like Alzheimer Disease?
Common disease Public interest Media coverage of genetic testing Direct marketing of molecular genetic testing
to physicians and the public Patients will turn to health care providers for
information and advice
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Dementia
Alzheimer disease– accounts for 2/3 of cases– majority of familial cases
Mixed Alzheimer and vascular Vascular Other
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Alzheimer Disease - Clinical
Slow progressive course of loss of cognitive functions:– memory – communication skills– judgement and reasoning
Significant impairment of social and occupational functioning– behavioural problems
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Alzheimer Disease - Pathology
Neuronal loss
Deposition of amyloid in senile plaques (arrow*) and cerebral blood vessels
Neurofibrillary tangles in neurons of cerebral cortex and hippocampus
* http://pathology.ouhsc.edu/DeptLabs/alzheimer_neuritic.htm
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Alzheimer Disease Risk Factors
Age
Family history
Down syndrome
Cognitive impairment
Low education
Head injury
HRT
Aluminum (?)
Physical inactivity
Other
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“My father has Alzheimer disease. Can I be tested to see if I carry the gene?”
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Family History of AD Work-Up
Detailed 3-generation pedigree
Specific symptoms– age of onset– number of unaffected relatives
Medical records including autopsy
Is it Alzheimer disease or some other condition?
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Treatable causes of cognitive decline Depression
Chronic drug intoxication
Chronic CNS infection
Thyroid disease
Vitamin deficiencies (e.g. B12 and thiamine)
CNS angiitis
Normal pressure hydrocephalus
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Other familial early-onset dementias…
Frontotemporal dementia with parkinsonism -FTDP-17– Suspect when FTD is familial (approx 10-40%)– May have dementia and/or parkinsonism– Onset usually 40-60 years
Huntington disease
Prion diseases
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…Other familial early-onset dementias
CADASIL - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
Dementia with Lewy bodies
Other rare conditions
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85 87
90 88 86 83 80
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85 87
90 88 86 83 80
45 What is the cause?
sporadic
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85 87
90 88 86 83 80
45 What is the chance your patient will develop AD?
~15-25%
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Risks to First Degree RelativesRough rule of thumb: Risk to first-degree relatives of
an affected individual is increased 3 to 4 times relative to risk in controls up to age 85
Prevalence of dementia by age
Age (years) Prevalence of dementia (%) 65-69 1.5
70-74 3.5
75-79 6.8
80-84 13.6
85-89 22
90-94 32
95-99 45
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85 87
90 88 86 83 80
45Is genetic testing
possible?
No
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85 87dx 78
90 88dx 83
86 83 80
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What is the cause?
chance occurrence
85 87dx 78
90 88dx 83
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single major gene
complex inheritance
85 87dx 78
90 88dx 83
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What is the chance your patient will develop AD?
unknown, but likely up to 50%
85 87dx 78
90 88dx 83
86 83 80
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85 87dx 78
90 88dx 83
86 83 80
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Is genetic testing possible?option of participating in research for late-onset AD, if 2 affected relatives available to give samples
85 87dx 78
90 88dx 83
86 83 80
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85 87dx 78
90 88dx 83
86 83 80
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52dx 45
85 51dx 44
60 55 50dx 45
49dx 42
25
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85 51dx 44
52dx 45
60 55 50dx 45
49dx 42
What is the cause?
major gene
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85 51dx 44
52dx 45
60 55 50dx 45
49dx 42
What is the chance your patient will develop AD?
50%
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85 51dx 44
52dx 45
60 55 50dx 45
49dx 42
Is genetic testing possible?
YES
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Sporadic • 75%
• majority late-onset
• same symptoms as
familial
Familial• less than 5% early-onset,
single gene inheritance
•15-25% late-onset, complex
inheritance
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Genetics of Familial Early-OnsetAlzheimer Disease
Chromosome Gene Age of Onset Proportion of Affected Families
21 APP early 50’s 5%
14 presenilin1 40’s (28-65) 50%
1 presenilin2 40’s (40-85) Rare
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bb Bb
Bb bb Bb bb
Alzheimer disease
Autosomal Dominant Inheritance
Population Risk
Population Risk
Alzheimer disease
Unaffected
Legend
B: Alzheimer gene with mutation
b: normal Alzheimer gene
Alzheimer disease
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Late-Onset Alzheimer DiseaseRisk Modifier Genes
Chromosome Gene Effect
19 ApoE 4: age of onset
12 A2M A2M-2: risk of developing AD
Information current as of April 2005. For an updated list of genetic tests refer to http://www.genetests.org
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Apolipoprotein E
Gene encoding apolipoprotein E associated with Alzheimer disease
3 alleles: 2, 3, 4
ApoE 4 – increases risk by decreasing age of onset,
especially when 2 copies are present
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ApoE Genotyping
Pre-symptomatic testing for 4 not recommended – low sensitivity and specificity– 2% of population are homozygotes– 4 neither necessary nor sufficient for the disease
Role as a diagnostic aid is controversial– 42% of patients with AD do not have an 4 allele
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ApoE4 allele frequency in dementia subtypes*
Non-demented control 12.3 %
Alzheimer disease 32.1 %
Vascular dementia 15.3 %
Mixed dementia 24.3 %
Non-AD/ non-VD dementia 16.7 %
Lewy body dementia 37.3 %
*Bang OY et al. 2003
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ApoE and CIND
ApoE 4 genotype– Significant risk factor for conversion from CIND to AD– Not a significant risk factor for conversion from normal
to CIND– Associated with decrease in age of onset of AD
Predictive values do NOT support its utility as diagnostic test for predicting progression from CIND to AD
Hsiung et al. CMAJ 2004
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ComplexInheritance
Visual Aids for Educators & Health Care Providers on Genetics: www.cclbooks.com
Unaffected Unaffected Affected
Environmental factor
Genetic factor
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ComplexInheritance
Genetic factor
Environmental factor
Visual Aids for Educators & Health Care
Providers on Genetics: www.cclbooks.com
Unaffected Unaffected Affected
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Key information for concerned patients…
Hereditary vs. Sporadic
Late-onset vs. Early-onset
Compare risk of developing AD:– general population– individual
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… Key information for concerned patients
Genetic testing possible? Discuss ApoE and why not useful Future advances
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Genetic Testing for Familial Alzheimer Disease
Confirmation of diagnosis
Predictive (pre-symptomatic)
Susceptibility
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Genetic Testing for Symptomatic Alzheimer Disease
May be useful as a diagnostic test for early-onset cases
Search for a mutation in the symptomatic patient precedes testing the unaffected relative
A negative test does not eliminate potential inherited cause
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Pre-symptomatic Testing for FADLessons Learned from
Huntington Disease
Minority of at-risk individuals seek testing Importance of pre- and post-test genetic
counselling, professional and family support Small proportion develop adverse
psychological effects
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Points to Consider for Predictive Testing
Informed choice, no coercion Reasons for knowing, not knowing Effects on family Potential for discrimination Testing in childhood Prenatal testing Consider genetics consultation
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Genetic Testing Criteria for Alzheimer Disease
For affected individual: onset under 60 years
For unaffected individual: two close relatives on same side of the family (one should be parent or sib) affected with early-onset AD (all affected are deceased)
Research only testing: 2 or more living affected family members with onset greater than 60 years
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Laboratories Offering Genetic Testing for Alzheimer Disease
Research: Centre for Research in Neurodegenerative Diseases, University of Toronto -Dr. Peter St. George-Hyslop
– all genes depending on clinical presentation Service: Athena Diagnostics Inc. -
Presenilin1, ApoE- cost for Presenilin1: $1,095 US- cost for ApoE genotyping: $299 US
Current as of March 2005. For up-to-date information on new genetics tests contact your local genetics clinic or http://www.genetests.org.
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Maintaining brain health...
Stay mentally active Stay physically active Remain, or become, socially engaged Get enough sleep Take multivitamin that has B12, B6 and folate
after age 50 Avoid excessive alcohol Avoid head injury -seatbelts, helmets
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…Maintaining brain health
Reduce risk for cardiovascular disease– treat hypertension, high cholesterol, diabetes– stop smoking
Treat depression, reduce stress & anxiety Treat hypothyroidism Treat pain Watch medication dosage and drug
interactions
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Key Points
Early-onset familial Alzheimer disease…
<5% of all AD
Genetic testing available– may be helpful in diagnosis and prediction of
disease
Importance of informed choice
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Key Points
...Early- onset familial Alzheimer disease
Benefits to patient – knowledge, relief from uncertainty for those who
want to know, life planning
Risks to patient – anxiety, depression, insurance/employment
discrimination, effects on family, effects on relationships
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Key Points
Late-onset familial Alzheimer disease
– 20% of all AD
– No testing available • possible exception of diagnostic testing for ApoE 4
(presymptomatic testing not recommended)
– Future research will target therapy to individual genetic make-up
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Additional Resources…
Local genetics clinics– Consider referral if family meets testing criteria– http://www.cagc-accg.ca/centre1.html
Alzheimer Society of Canada– www.alzheimer.ca
Familial Alzheimer Disease Registry, University of Toronto – www.utoronto.ca/crnd
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…Additional Resources
www.phgu.org.uk – UK Public Health Genetics Unit– Educational resource on genetics
http://murdoch.rch.unimelb.edu.au/GF/pages/GeneticsFile.asp – “The Genetics File” - a GP resource on genetics
http://www.mtsinai.on.ca/FamMedGen/Default.htm – Description of disorders and helpful links
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Resources for Patients
http://www.alzheimer.ca/english/disease/causes-heredity.htm – Alzheimer Society of Canada
http://www.alz.org/Resources/FactSheets/FSGenetics.pdf – Alzheimer’s Association– About genes and AD
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The Genetics Education Project Committee
June Carroll MD CCFP Judith Allanson MD FRCP
FRCP(C) FCCMG FABMG Sean Blaine MD CCFP Mary Jane Esplen PhD RN Sandra Farrell MD FRCPC
FCCMG Judy Fiddes Gail Graham MD FRCPC
FCCMG Jennifer Mackenzie MD
FRCPC FAAP FCCMG
Wendy Meschino MD FRCPC FCCMG
Joanne Miyazaki Andrea Rideout MS CGC
CCGC Barbara Slater Cheryl Shuman MS CGC Anne Summers MD FCCMG
FRCPC Sherry Taylor PhD FCCMG Brenda Wilson BSc MB ChB
MSc MRCP(UK) FFPH
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References1. The American Society of Human Genetics Board of Directors
and The American College of Medical Genetics Board of Directors. ASHG/ACMG REPORT Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. Am J Hum Genet 1995;57:1233-1241.
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3. Erkinjuntti T. Vascular dementia: an overview. In Dementia, 2nd edition. O’Brien J, Ames D and Burns A, editors. Arnold Publishers, London, 2000: 685-97.
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Becker R, Burke J, Chui H, Duara R, Foley EJ, Glatt SL, Green RC, Jones R, Karlinsky H, Kukull WA, Kurz A, Larson EB, Martelli K, Sadovnick AD, Volicer L, Waring SC, Growdon JH, Farrer LA. Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 1996;46(3):641-50.
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References28. Modified from Campbell-Lashley C. Visual Aids for
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