115 Risk of dementia related to APOE ε4 and a polygenic risk score ɛ4 allele was especially associated with a higher risk of AD dementia (HR 3.3 (1.7-6.3)), but not other types of dementia (HR 1.0 (0.4-2.3)). When we repeated the analyses with APOE and PRS both as predictors in the models, the relationship between the PRS and progression to AD dementia was not significant anymore, but results for APOE remained comparable (Supplementary Table 3). Table 2. Association between genetic variants and risk of clinical progression PRS APOE ε4 N HR (95% CI) p-value HR (95% CI) p-value Non-dementia 450 All-type dementia 41 1.0 (0.7-1.4) 9.6x10-1 2.0 (1.3-3.2) 3.7x10-3* AD dementia 25 1.7 (1.1-2.8) 2.8x10-2* 3.3 (1.7-6.3) 4.6x10-4* Other dementia 16 0.5 (0.3-0.9) 2.2x10-2* 1.0 (0.4-2.3) 9.8x10-1 Values are obtained by Cox proportional hazard models, adjusted for age, sex, population substructure and MMSE (predictor: APOE ε4 allele or normalized PRS, outcome: clinical progression to dementia. The HR associated with the PRS reflects the difference per one standard deviation increase in the PRS. APOE ε4 is per allele. * p-value <0.05. PRS = polygenic risk score; HR = hazard ratio; CI = confidence interval; AD = Alzheimer’s disease. Next, we investigated the combined effect of APOE ε4 and PRS on risk of dementia. Based on a newly constructed four level variable (APOEε4-PRSlow as reference), we found that APOEε4+PRShigh had a higher risk of progression to AD dementia (Table 3, Figure 3). By contrast, in APOEε4+PRSlow the risk of progression was attenuated and became comparable to APOEε4-PRShigh. There were no associations with progression to all-type dementia or non-AD dementia. 5
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