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  • 1. Genetics of Alzheimer Disease: An Overview Murugu Manickam, MD discloses no significant financial interests or other relationships with commercial interests. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device. Murugu Manickam, MD Clinical Assistant Professor Division of Human Genetics
  • 2. Alzheimer Disease
    • Increasingly prevalent disorder characterized by dementia, loss of executive functions, memory loss, agitation, withdrawal
      • Likely increased incidence is because of longer life span
    • Subtle changes at onset can proceed more severe symptoms by a months or a decade
    • Duration is typically 8-10 years
  • 3. Alzheimer Disease
    • Diagnosis is typically clinical based on slowly progressive dementia
    • Head imaging may show cortical atrophy
    • Increasing use of PET scans
    • Typical feature seen on autopsy of amyloid plaques, tau tangles
  • 4. Genetics and Alzheimer Disease
    • There are multiple causes based on age of onset
    • Early onset (less than 60): rare- less than 2% of all AD cases
        • Associated with genetic changes in PSEN1, PSEN2, APP
        • Autosomal dominant pattern of inheritance
        • High penetrance- nearly 100% by age 60
  • 5. Genetics and Alzheimer Disease
    • Early onset due to Down syndrome
    • Also increasing prevelance as children with Down syndrome (trisomy 21) are becoming adults with Down syndrome
    • Appears to be related to gene dosage from an extra copy of a gene on 21
    • 25% by age 35, odds ratio of 3x-5x greater than the general population (compared to older adult population)
  • 6.
    • Late onset (after age 65) 75-90% of all cases
      • Clearly strong genetic predisposition but few genes known (25% of patients will have 2 or more relatives also affected)
      • Can have a mix of early onset and late onset in the family
      • Twin studies have shown a combination of genetic susceptibility and environment but poorly defined
    Genetics and Alzheimer Disease
  • 7. ApoE
    • Apolipoprotein E (ApoE)
      • Responsible for removal of cholesterol from the bloodstream
      • Normal type ApoE-3
        • ApoE2- single base change (SNP rs7412)
        • ApoE4- two base changes (SNP rs429358 and rs7412)
    Allele Population E3/E3 55% E3/E4 25% E3/E2 15% E2/E4 1-2% E2/E2 1-2% E4/E4 1-2%
  • 8. ApoE
    • E4/E4 variant confers a 25x increased risk for development of AD by age 75
      • Specifically in Caucasian and Japanese populations (less in others)
      • Likely related to poor breakdown of beta-amyloid
      • E3/E4 also have increased risk but not as high
  • 9. ApoE
    • E2/E2 variant appears to be protective with less AD seen compared to other combinations
    • Interestingly, E2/E4 is equivalent to E3/E3 (or population risk)
  • 10. ApoE
    • However, E4/E4 only explains a small proportion of AD and many patients with E4/E4 do not develop AD
    • Additionally there appears to minor effects from other SNPs including a very strong effect from POLD1 gene (OR: 10)
  • 11. ApoE and Cardiovascular Disease
    • However, E4/E4 only explains a small proportion of AD and many patients with E4/E4 do not develop AD
    • Additionally there appears to minor effects from other SNPs including a very strong effect from POLD1 gene (OR: 10)