117 Risk of dementia related to APOE ε4 and a polygenic risk score Table 3. Combined effect of APOE ɛ4 and PRS on risk of clinical progression to AD dementia Progression to all-type dementia Progression to AD dementia Progression to non-AD dementia Category Total N HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value APOE ɛ4 noncarrier Low PRS 158 Ref Ref Ref Ref Ref Ref APOE ɛ4 noncarrier High PRS 134 0.5 (0.1-1.8) 2.8x10-1 1.7 (0.3-11.1) 5.9x10-1 0.1 (0.0-1.0) 5.1x10-2 APOE ɛ4 carrier Low PRS 86 0.9 (0.3-2.3) 7.6x10-1 2.4 (0.3-18.0) 3.9x10-1 0.8 (0.2-3.2) 7.5x10-1 APOE ɛ4 carrier High PRS 109 1.7 (0.7-3.9) 2.5x10-1 4.8 (1.2-18.9) 2.6x10-2* 0.4 (0.1-1.8) 2.2x10-1 Values are obtained by Cox proportional hazard models, adjusted for age, sex, population substructure and MMSE (predictor: four-level variable (1) APOE ɛ4 non-carrier and low PRS, (2) APOE ɛ4 non-carrier and high PRS, (3) APOE ɛ4 carrier and low PRS and (4) APOE ɛ4 carrier and high PRS; outcome: clinical progression to dementia; reference: (1) APOE ɛ4 non-carrier and low PRS). APOE ε4 status is determined by having one or two ε4 alleles, PRS status is based on median risk. * p-value <0.05. AD = Alzheimer’s disease, HR = hazard ratio, CI = confidence interval; PRS = polygenic risk score. DISCUSSION The main finding of this study is that an Alzheimer’s disease polygenic risk score predicts biomarker pathology when distributed according to the ATN biomarker classification, independently of APOE. Furthermore, both APOE ɛ4 and the PRS are associated with risk of AD dementia. When combined we found that only carriers of the APOE ɛ4 allele who also had a high PRS specifically progressed to AD dementia, implying that the increased risk of APOE ɛ4 carriers can be ‘undone’ by having a low PRS. 5