Alzheimer disease

Developed by Dr. June Carroll, Ms. Shawna Morrison and Dr. Judith Allanson

Last updated April 2015

Disclaimer

• This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.

Objectives• Following this session the learner will be able to:– Refer to their local genetics centre and/or order genetic

testing appropriately for Alzheimer disease (AD)– Discuss and address patient concerns regarding AD– Find high quality genomics educational resources

appropriate for primary care

Case 1

• Mary, 25yo female in good health

• Concerned about her risk of Alzheimer disease (AD) as her father’s condition is worsening quickly

ADdx 55

d.85

ADdx53

AD dx 61

25

d.65

ADdx 57

63 58 5560d.68

A&W A&W

A&W

Stroke

Case 2

• Mandy, 55yo female in good health

• Concerned about her risk of Alzheimer disease due to her father’s recent diagnosis

MI

ADdx 80

88 8690 75

55

80

d.87d.85

arthritis IDDM

A&W

Case 3

• Morgan, 55yo female in good health

• Concerned about her risk of Alzheimer disease due to her father’s recent diagnosis and family history

ADdx78

ADdx 80

d.88 8690 75

55

80

d.87d.85

AD dx83

IDDM

A&W

What is Alzheimer disease?• Alzheimer disease (AD) is an adult-onset progressive

dementia that gradually reduces a person’s memory and ability to learn, reason, make judgments, communicate and carry out daily activities. Individuals may also experience changes in personality and behaviour

• General population lifetime risk of developing dementia is 10-12%

Sporadic, late onset, unknown cause

Late-onset familial AD (LOAD)has a mean age of onset of >60-65years (15-25%)

Early-onset familial AD (EOAD) hasa mean age of onset < 60-65 years(<2%)

• Early-onset AD (EOAD) has an autosomal dominant inheritance pattern

• Three genes have been associated with EOAD:– amyloid precursor protein (APP)– presenilin 1 (PSEN1)– presenilin 2 (PSEN2)

• Each of these genes is involved in production of the amyloid ß (Aß) peptide, a major component of amyloid plaques

What do I need to know about the genetics of Alzheimer disease?

What do I need to know about the genetics of Alzheimer disease?

• Late-onset familial AD (LOAD) has been associated with apolipoprotein E (APOE)

• APOE is considered a risk modifier, especially APOE 4

• Approximately 1% of the general population are APOE 4 homozygotes (carry two copies of 4)

• Approximately 42% of persons with AD do NOT have an APOE 4 allele

• APOE 4 is neither necessary nor sufficient to cause LOAD

What do I need to know about the genetics of Alzheimer disease?

• Alzheimer disease (AD) develops due to a complex interaction between genetic and environmental factors

• With one affected first-degree relative, the risk of Alzheimer disease is approximately 20-25% (approximately double the population risk)

Who should be offered referral for genetic consultation?

Consider a genetics consult for:Patients with Alzheimer disease (AD) with onset <60-

65 yearsPatients with late-onset AD and multiple affected

close relativesClose relatives of the above two types of patientsA member of a family in which there is an identified

mutation in the APP, PSEN1 or PSEN2 genes

Who will be offered genetic testing and what do the test results mean?

• Genetic testing for Alzheimer disease (AD) is only available for a small number of families with early-onset AD (EOAD)– Testing likely to be initiated in a living affected

relative• If a gene mutation is found, other family members

are eligible for testing focused on the identified family mutation– Inheriting a mutation in APP, PSEN1 or PSEN2

gene causes early-onset Alzheimer disease (EOAD)

• Clinical testing is currently not available for late-onset AD (LOAD) or sporadic cases

• When there are multiple related affected individuals, research testing may be available

• APOE 4 testing is not recommended for risk assessment because of low sensitivity and specificity

• APOE 4 is neither necessary nor sufficient for the disease

Who will be offered genetic testing and what do the test results mean?

How will genetic testing help you and your patient?

• In the case of genetic testing for early-onset Alzheimer disease (EOAD), – A positive test result for a known family gene mutation

can result in:• Relief from uncertainty• An increased feeling of control• Opportunity to plan life decisions

– A negative test result for a known family gene mutation can result in:• Relief from fear of developing EOAD• Knowledge that children are not at risk for EOAD

Are there harms or limitations of genetic testing?

• Currently no cure or effective preventive therapy is available if a gene mutation is found

• In the case of genetic testing for early-onset Alzheimer disease (EOAD), – A positive test result for a known family gene mutation

can result in:• Adverse psychological reaction, family issues/distress• Insurance/job discrimination, confidentiality issues

– A negative test result for a known family gene mutation can result in survivor guilt

Case 1

ADdx 55

d.85

ADdx53

AD dx 61

25

d.65

ADdx 57

63 58 5560d.68

A&W A&W

A&W

Stroke

Case 1

• Family history is suggestive of early-onset AD (EOAD – dx<60-65y) and dominant inheritance pattern

• Offer referral for genetics consultation with option of genetic testing

ADdx 55

d.85

ADdx53

AD dx 61

25

d.65

ADdx 57

63 58 5560d.68

A&W A&W

A&W

Stroke

Case 2

MI

ADdx 80

88 8690 75

55

80

d.87d.85

arthritis IDDM

A&W

Case 2

• Family history is suggestive of sporadic AD

• Mandy’s AD risk is about 20-25% because of an affected FDR

• No referral to genetics indicated

MI

ADdx 80

88 8690 75

55

80

d.87d.85

arthritis IDDM

A&W

Case 3

ADdx78

ADdx 80

d.88 8690 75

55

80

d.87d.85

AD dx83

IDDM

A&W

Case 3

• Family history suggestive of late-onset AD (LOAD)

• Referral to genetics can be considered for counselling and personal risk estimation

• No genetic testing is available but participation in research may be possible

ADdx78

ADdx 80

d.88 8690 75

55

80

d.87d.85

AD dx83

IDDM

A&W

Pearls

•Informative genetic testing is currently available to only a small number of families with early-onset (<60-65 years of age) Alzheimer disease (EOAD)

•Genetic testing is not possible for most cases of AD

•Apolipoprotein E gene variations alone cannot be used to predict risk of developing AD

References• Alonso Vilatela ME et al., Genetics of Alzheimer’s disease. Arch Med Res.

2012; 43(8): 622-31 and Goldman JS et al., Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 2011; 13(6): 597-605

• American College of Medical Genetics/American Society of Human Genetics Working Group on APOE and Alzheimer's disease (1995) Statement on use of apolipoprotein E testing for Alzheimer's disease. JAMA 1995; 274(20): 1627-1629

• Bird TD. Alzheimer Disease Overview. 1998 Oct 23 [Updated 2014 Jan 30]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1161/

• Genetics Education Project