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.

The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA

Murugu Manickam, MDClinical Assistant ProfessorDivision of Human Genetics

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

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

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

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)

• 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

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%

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

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)

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)

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)