The Genetics Education Project The Genetics of Alzheimer Disease Wendy S Meschino MD FRCPC FCCMG Clinical Geneticist, North York General Hospital Assistant

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


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.


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


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


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


Dementia

Alzheimer disease– accounts for 2/3 of cases– majority of familial cases

Mixed Alzheimer and vascular Vascular Other


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


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


Alzheimer Disease Risk Factors

Age

Family history

Down syndrome

Cognitive impairment

Low education

Head injury

HRT

Aluminum (?)

Physical inactivity

Other


“My father has Alzheimer disease. Can I be tested to see if I carry the gene?”


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?


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


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


…Other familial early-onset dementias

CADASIL - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Dementia with Lewy bodies

Other rare conditions


45

85 87

90 88 86 83 80


85 87

90 88 86 83 80

45 What is the cause?

sporadic


85 87

90 88 86 83 80

45 What is the chance your patient will develop AD?

~15-25%


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


85 87

90 88 86 83 80

45Is genetic testing

possible?

No


85 87dx 78

90 88dx 83

86 83 80

45


What is the cause?

chance occurrence

85 87dx 78

90 88dx 83

86 83 80

45

single major gene

complex inheritance

85 87dx 78

90 88dx 83

86 83 80

45


What is the chance your patient will develop AD?

unknown, but likely up to 50%

85 87dx 78

90 88dx 83

86 83 80

45

85 87dx 78

90 88dx 83

86 83 80

45


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

45

85 87dx 78

90 88dx 83

86 83 80

45


52dx 45

85 51dx 44

60 55 50dx 45

49dx 42

25


25

85 51dx 44

52dx 45

60 55 50dx 45

49dx 42

What is the cause?

major gene


25

85 51dx 44

52dx 45

60 55 50dx 45

49dx 42

What is the chance your patient will develop AD?

50%


25

85 51dx 44

52dx 45

60 55 50dx 45

49dx 42

Is genetic testing possible?

YES


Sporadic • 75%

• majority late-onset

• same symptoms as

familial

Familial• less than 5% early-onset,

single gene inheritance

•15-25% late-onset, complex

inheritance


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


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


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


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


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


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


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


ComplexInheritance

Visual Aids for Educators & Health Care Providers on Genetics: www.cclbooks.com

Unaffected Unaffected Affected

Environmental factor

Genetic factor


ComplexInheritance

Genetic factor

Environmental factor

Visual Aids for Educators & Health Care

Providers on Genetics: www.cclbooks.com

Unaffected Unaffected Affected


Key information for concerned patients…

Hereditary vs. Sporadic

Late-onset vs. Early-onset

Compare risk of developing AD:– general population– individual


… Key information for concerned patients

Genetic testing possible? Discuss ApoE and why not useful Future advances


Genetic Testing for Familial Alzheimer Disease

Confirmation of diagnosis

Predictive (pre-symptomatic)

Susceptibility


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


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


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


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


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.


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


…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


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


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


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


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


…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


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


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


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.

2. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales: MRC CFAS. The Lancet 2001; 357: 169-75.

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.


References

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5. Tanzi RE, Bertram L. New frontiers in Alzheimer’s disease genetics. Neuron 2001; 32: 181-84.

6. Lanctot KL, Herrman N, Yau KK, Khan LR, Liu BA, Loulou MM et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta- analysis. Can Med Assoc J 2003; 169: 557-64.


References

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8. The Canadian Study on Health and Aging Working Group: Canadian Study of Health and Aging: study methods and prevalence of dementia. Can Med Assoc J 1994; 150: 899-913.

9. Schupf N, Sergievsky. Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 2002;180:405-10.


References

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12. Lanctot KL, Herrman N, Yau KK, Khan LR, Liu BA, Loulou MM et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta- analysis. Can Med Assoc J 2003; 169: 557-64.


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McDowell I. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 2002; 156(5):445-53.

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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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References

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References

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References28. Modified from Campbell-Lashley C. Visual Aids for

Educators & Health Care Professionals on Genetics. 2000. CCL Books, Bloomington, MN. Also available at www.cclbooks.com.

29. Almqvist EW, Brinkman RR, Hayden MR, and the Canadian Collaborative Study of Predictive Testing (Nicolson Klimek ML, Trew M, Suchowersky O, Grover S, Bamforth S, Adam S, Huggins M, Bloch M, Green T, Greenberg C, Ives E, Fuller A, Welch P, Eisenberg D, Whelan D, Kane J, Soltan H, MacGregor D, Summers A, Meschino W, Prevost C, Dufrasne S, Roy M, Rosenblatt D, Cardwell S, Gibson A, Shokeir MHK). Psychological consequences and predictors of adverse events in the first five years after predictive testing for Huntington disease. Clin Genet (in press).


References

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The Genetics Education Project The Genetics of Alzheimer Disease Wendy S Meschino MD FRCPC FCCMG Clinical Geneticist, North York General Hospital Assistant