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=2,930) and Alzheimer’s Disease (AD) cases (N=1,760). Employing superagers, we see a nearly five 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 non-carriers. More specifically, PRS non-APOE in the top decile predicts an age-at-onset five years earlier compared to 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. Disclosure Statement AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics and GSK. She also served on the SAB at Denali Therapeutics from 2015-2018. YFH co-owns stock and stock options of Regeneron Pharmaceuticals. All other authors have no interests to declare.