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 AD dx 55 d.85 AD dx53 AD dx d.65 AD dx d.68 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 AD dx d.87 d.85 arthritisIDDM 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 AD dx78 AD dx 80 d d.87 d.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 %

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?

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 years Patients with late-onset AD and multiple affected close relatives Close relatives of the above two types of patients A 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 AD dx 55 d.85 AD dx53 AD dx d.65 AD dx d.68 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 AD dx 55 d.85 AD dx53 AD dx d.65 AD dx d.68 A&W Stroke

Case 2 MI AD dx d.87 d.85 arthritisIDDM 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 AD dx d.87 d.85 arthritisIDDM A&W

Case 3 AD dx78 AD dx 80 d d.87 d.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 AD dx78 AD dx 80 d d.87 d.85 AD dx83 IDDM A&W

Pearls Informative genetic testing is currently available to only a small number of families with early-onset (< 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): 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): 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): Statement Bird TD. Alzheimer Disease Overview Oct 23 [Updated 2014 Jan 30]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; Available from: Genetics Education Project