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

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.