Unequal expression: Social position modulates APOE genotype risk of dementia

Although social position plays a pivotal role in cognitive aging, most dementia prevention strategies and risk prediction models continue to emphasize biomedical and genetic factors (particularly APOE status). This disconnect raises critical questions about how social environments may shape the effect of genetic risk on dementia. We examined how APOE alleles interact with social adversity to determine dementia risk.

We conducted an observational analysis using two large cohort studies-the Health and Retirement Study (HRS) and the English Longitudinal Study of Ageing (ELSA)-including individuals aged 55 years or older without dementia at baseline. A social adversity index was constructed based on the five domains of social determinants of health outlined in the Healthy People 2030 framework: education access, economic stability, healthcare quality, neighborhood environment, and social context. Participants were classified as having low (APOE-ε2), intermediate (APOE-ε3/ε3), or high (APOE-ε4) genetic risk of dementia. Dementia was ascertained via clinical diagnosis, cognitive testing, or validated caregiver report. Cox proportional hazards models were used in each cohort, and estimates were pooled using random-effects adjusting for covariates.

A total of 9,849 participants (HRS = 5,797; ELSA = 4,052) were followed for up to 12 years. Genetic effects were most pronounced among individuals with social advantage (reference: APOE-ε3/ε3 with social advantage; APOE-ε2 HR = 0.67, 95%CI = 0.48-0.93; APOE-ε4 HR = 1.68, 95%CI = 1.37-2.06). In contrast, those experiencing high social adversity had elevated dementia risk regardless of genotype (reference: APOE-ε3/ε3 with social advantage; APOE-ε2 HR = 3.26, 95%CI = 2.06-5.16; APOE-ε3/ε3 HR = 3.12, 95%CI = 2.47-3.95; APOE-ε4 HR = 3.21, 95%CI = 2.34-4.41). Notably, individuals with high genetic risk but social advantage had a lower dementia risk than those with low genetic risk but high social adversity.

The influence of genetic risk on dementia appears shaped by social position. Addressing social adversity may reduce dementia risk across genotypes and enhance equity in dementia prevention strategies.