Polygenic score modifies risk for Alzheimer's disease in <i>APOE</i> ε4 homozygotes at phenotypic extremes
Aamira Huq, Brian Fulton‐Howard, Moeen Riaz, Simon M. Laws, Robert Sebra, Joanne Ryan, Alan E. Renton, Alison Goate, Colin L. Masters, Elsdon Storey, Raj C. Shah, Anne R. Murray, John J. McNeil, Ingrid Winship, Paul A. James, Paul Lacaze
Abstract
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.