Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring (Jan 2021)

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

  • Aamira J. Huq,
  • Brian Fulton‐Howard,
  • Moeen Riaz,
  • Simon Laws,
  • Robert Sebra,
  • Joanne Ryan,
  • Alzheimer's Disease Genetics Consortium,
  • Alan E. Renton,
  • Alison M. Goate,
  • Colin L. Masters,
  • Elsdon Storey,
  • Raj C. Shah,
  • Anne Murray,
  • John McNeil,
  • Ingrid Winship,
  • Paul A. James,
  • Paul Lacaze

DOI
https://doi.org/10.1002/dad2.12226
Journal volume & issue
Vol. 13, no. 1
pp. n/a – n/a

Abstract

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Abstract Introduction Diversity in cognition among apolipoprotein E (APOE) 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 APOE ε4 homozygotes aged ≥75 years (n = 213) and early‐onset APOE ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results The PRS for AD was significantly higher in APOE ε4 homozygote AD cases compared to older cognitively healthy APOE ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0–35.2; P = .003). The difference in the same PRS between APOE ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98–9.92; P = .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 APOE ε4/ε4 genotype at phenotypic extremes of risk.

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