To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRS), we estimated PRS 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 decile to the lowest decile (OR = 4.82, p = 2.5 × 10), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10). Thus PRS is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRS modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRS 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) among APOE4 carriers. This disproportionally large PRS 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) as a predictor of PRS. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.