113 Risk of dementia related to APOE ε4 and a polygenic risk score Associations between the PRS, APOE ɛ4 and biomarkers Using logistic regression models, we found that higher PRS was associated with increased likelihood of amyloid positivity (OR 1.5 (95% CI 1.2-2.0), Figure 2A), but not of tau positivity (OR 1.1 (0.9-1.4)) or positivity for neurodegeneration (OR 1.0 (0.8-1.3)). APOE ɛ4 was associated with both amyloid positivity (OR 3.5 (2.5-5.1), per allele) and tau positivity (OR 1.6 (1.2-2.1)), but not positivity for neurodegeneration (OR 1.4 (1.0-2.0)). When performing multinomial logistic regression with the eight-profile ATN classification as outcome, we found that the PRS was associated with an increased likelihood of A+T-N- and A+T+N- compared to A-T-N- (OR 1.9 (1.3-2.9) and OR 1.8 (1.22.6), Figure 3B). APOE ɛ4 was associated with all A+ profiles, except for A+T+N+ (n=6), as well as with an isolated abnormal tau (A-T+N-, OR 1.5 (1.0-2.3)). Since the eightprofile ATN classification comes with suboptimal power due to small sample sizes in certain profiles, we repeated the analyses with the three-category ATN classification as outcome. We found that a higher PRS was associated with higher odds of being classified in the Alzheimer’s continuum (OR 1.6 (1.2-2.2)), but not with higher odds of non-AD pathologic change (OR 1.1 (0.9-1.4)). APOE ɛ4 on the other hand, was associated with both Alzheimer’s continuum (OR 4.2 (2.6-6.7)) and non-AD pathologic change (1.5 (1.1-2.2)). When we repeated the analyses with APOE and PRS both as predictors in the models, results remained comparable (Supplementary Table 2). 5