Polygenic score modifies risk for Alzheimer's disease in ε4 homozygotes at phenotypic extremes.

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TitlePolygenic score modifies risk for Alzheimer's disease in ε4 homozygotes at phenotypic extremes.
Publication TypeJournal Article
Year of Publication2021
AuthorsHuq AJ, Fulton-Howard B, Riaz M, Laws S, Sebra R, Ryan J, Renton AE, Goate AM, Masters CL, Storey E, Shah RC, Murray A, McNeil J, Winship I, James PA, Lacaze P
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalAlzheimers Dement (Amst)
Volume13
Issue1
Paginatione12226
Date Published08/2021
ISSN2352-8729
Abstract

Introduction: Diversity in cognition among apolipoprotein E () ε4 homozygotes can range from early-onset Alzheimer's disease (AD) to a lifetime with no symptoms.

Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy ε4 homozygotes aged ≥75 years (n = 213) and early-onset ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity.

Results: The PRS for AD was significantly higher in ε4 homozygote AD cases compared to older cognitively healthy ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0-35.2;  = .003). The difference in the same PRS between ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98-9.92;  = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case-controls.

Discussion: A PRS for AD contributes to modified cognitive expression of the ε4/ε4 genotype at phenotypic extremes of risk.
DOI10.1002/dad2.12226
Alternate JournalAlzheimers Dement (Amst)
PubMed ID34386572
PubMed Central IDPMC8339682
Grant ListU01 AG032984 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States