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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 d.85 Stroke d.68 AD dx 55 63 d.65 AD dx 57 60 58 AD A&W AD dx 61 dx53 25 A&W 55 A&W • Mary, 25yo female in good health • Concerned about her risk of Alzheimer disease (AD) as her father’s condition is worsening quickly Case 2 d.85 d.87 MI 90 arthritis 88 86 80 75 AD IDDM dx 80 55 A&W • Mandy, 55yo female in good health • Concerned about her risk of Alzheimer disease due to her father’s recent diagnosis Case 3 d.85 d.87 AD dx78 90 d.88 AD dx83 86 80 75 AD dx 80 IDDM 55 A&W • Morgan, 55yo female in good health • Concerned about her risk of Alzheimer disease due to her father’s recent diagnosis and family history 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 1012% Sporadic, late onset, unknown cause Late-onset familial AD (LOAD) has a mean age of onset of >60-65 years (15-25%) Early-onset familial AD (EOAD) has a mean age of onset < 60-65 years (<2%) What do I need to know about the genetics of Alzheimer disease? • 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 earlyonset 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) Who will be offered genetic testing and what do the test results mean? • Clinical testing is currently not available for lateonset 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 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 d.85 Stroke d.68 AD dx 55 63 d.65 AD dx 57 60 58 AD A&W AD dx 61 dx53 25 A&W 55 A&W Case 1 d.85 Stroke d.68 AD dx 55 63 d.65 AD dx 57 60 58 AD A&W AD dx 61 dx53 25 A&W 55 A&W • 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 Case 2 d.85 d.87 MI 90 arthritis 88 86 80 75 AD IDDM dx 80 55 A&W Case 2 d.85 d.87 MI 90 arthritis 88 86 80 75 AD IDDM dx 80 55 A&W • 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 Case 3 d.85 d.87 AD dx78 90 d.88 AD dx83 86 80 75 AD dx 80 IDDM 55 A&W Case 3 d.85 d.87 AD dx78 90 d.88 AD dx83 86 80 75 AD dx 80 IDDM 55 A&W • 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 Pearls • Informative genetic testing is currently available to only a small number of families with early-onset (<6065 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