Alzheimer disease Developed by Dr. June Carroll, Ms. Shawna Morrison and Dr. Judith Allanson Last updated Dec 2014

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 appropriately to their local genetics centre for Alzheimer disease – Discuss and address patient concerns regarding family history of Alzheimer disease – 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 the identified 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) gene variations These are 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

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 genetic testing and/or referral for genetic consultation? Consider a genetics consult for patients with: Alzheimer disease (AD) with age of onset <60-65 years Late-onset AD and multiple affected close relatives Close relationship to the above two types of patients A family member who has an identified mutation in the APP, PSEN1 or PSEN2 genes

What do the genetic 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 for 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 Information about the genetic factors involved is limited 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 What do the genetic 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 When an individual with no known familial gene mutation has genetic testing, a negative result is uninformative.

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 Family history is suggestive of sporadic type of AD Mandy’s AD risk is about 15-25% because of an affected FDR No referral to genetics indicated MI AD dx d.87 d.85 arthritisIDDM Mandy A&W

Case 3 Family history suggestive of late-onset AD (LOAD) Referral to genetics can be considered for counselling and personal risk estimation Option to participate in research may be available AD dx78 AD dx 80 d d.87 d.85 AD dx83 IDDM Morgan A&W

Pearls Informative genetic testing is currently available to only a small number of families with a history of early-onset (<60-65 years of age) Alzheimer disease (EOAD) – For these families, the benefits of genetic testing are limited and are mainly related to the individual’s perception of the psychological advantages of knowing whether or not he or she is predisposed to develop AD – There remains no cure or effective preventive therapy for AD Genetic testing is not feasible for most cases of AD at this time Families with multiple relatives affected with late-onset AD (>60-65 years of age) (LOAD) might be eligible to participate in AD research studies Apolipoprotein E gene variations alone cannot be used to predict future

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