Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers

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.