Heterogeneity in the association between APOE ε4 carrier status and dementia risk by modifiable and non-modifiable risk factors.
Dementia is a major public health challenge, and Apolipoprotein E (APOE) ε4 is strongly associated with all-cause dementia, particularly Alzheimer's disease (AD). We aim to quantify the overall contribution of modifiable lifestyle, adiposity, socioeconomic status (SES), and health conditions occurring before dementia, to the association between ε4 genotype and the development of all-cause dementia, with AD examined as a major subtype. A population cohort study of 181,006 white UK Biobank participants aged ≥ 55 years at baseline was conducted, to examine the associations between APOE ε4 and all-cause dementia, and specifically AD, including modification and mediation role of lifestyle factors, adiposity, SES, and health conditions occurring before dementia. All risk factors, except for high alcohol intake, low diet quality, and phenotypic obesity, were associated with higher risk of all-cause dementia. The interaction contributions of lifestyle, adiposity, SES, and health conditions occurring before dementia varied by sex and dementia type. Low educational attainment had the strongest interaction effects with the association of APOE ε4 carriers and AD/all-cause dementia (up to 32.1%). In women, high deprivation level, abnormal sleep duration, anxiety, and depression showed interaction effects with APOE genotype (5-11.6%) as well. Phenotypic adiposity was associated with an increased risk of dementia among APOE ε4 non-carriers, but with a reduced risk among APOE ε4 carriers. Educational attainment explained a meaningful proportion of the APOE ε4 association with dementia. The strength of the association between APOE ε4 and dementia differed by risk factors and sex.