Cardiometabolic diseases, polygenic risk score, APOE genotype, and risk of incident dementia: A population-based prospective cohort study.

Objective We aimed to prospective investigate the association between cardiometabolic diseases (CMDs) with dementia, and to examine whether genetic factors and CMDs jointly contribute to the incidence of dementia. Methods We used data from the UK biobank of 204,646 adults aged 37-73 free of dementia at baseline. Genetic risk for dementia including APOE ε4 status and polygenic risk score (PRS) categorized as low, intermediate, and high. CMDs including ischemic heart disease (IHD), stroke, and type 2 diabetes (T2D) were confirmed by touchscreen questionnaires, medical examinations, and hospital inpatient records. Results Over the follow-up (median: 12.5 years), 5,750 participants developed dementia. The HRs (95% CI) of those with APOE ε4 carriers and high PRS were 3.16 (3.00-3.33) and 1.50 (1.41-1.60), respectively. The risk of dementia was 70% higher among those with CMDs (HR: 1.70; 95% CI: 1.60-1.82). In joint effect analyses, compared to no CMDs and APOE ε4 non-carriers, the HRs (95% CIs) of dementia were 3.53 (3.31-3.76)/2.06 (1.89-2.23) in participants with only APOE ε4 carriers and CMDs, and 5.06 (4.64-5.53) for those with APOE ε4 carriers plus CMDs. Compared to no CMDs and low PRS, the HRs (95% CIs) of dementia were 1.29 (1.19-1.40)/1.60 (1.48-1.73) in participants with only intermediate and high PRS, and 2.00 (1.79-2.23)/2.63 (2.38-2.92) for those with intermediate, and high PRS plus CMDs. Moreover, there were significant additive and multiplication interactions between CMDs and APOE ε4 carriers of dementia, but only multiplication interaction was observed for PRS. Conclusions CMDs were associated with higher risk of dementia regardless of genetic risk for dementia.