Abstract
To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRS(non-APOE)), we estimated PRS(non-APOE) in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRS(non-APOE) decile to the lowest decile (OR = 4.82, p = 2.5 × 10(-6)), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10(-9)). Thus PRS(non-APOE) is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRS(non-APOE) modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRS(non-APOE) in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10(-5)) among APOE4 carriers. This disproportionally large PRS(non-APOE) among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (β = -0.02, p = 4.8 × 10(-3)) as a predictor of PRS(non-APOE). Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.