Identifying the mediating role of inflammation on the relationship between socioeconomic status and Alzheimer's disease: a Mendelian randomization analysis and mediation analysis

Background and objectives: Observational studies have demonstrated a significant association between socio-economic status (SES) and Alzheimer's disease (AD). Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian Randomization (MR) approach to investigate the causal relationship between SES and genetic susceptibility to AD, as well as to explore the potential mediation effects of inflammation.

Methods: Large-scale cohorts based on publicly available genome-wide association study (GWAS) datasets from European populations were employed for conducting the MR study. The primary criterion utilized was the inverse-variance weighting (IVW) model. Heterogeneity and horizontal pleiotropy were assessed. In addition, multivariate MR (MVMR) was utilized to correct the confounders. Moreover, a two-step MR approach was used to evaluate the potential mediating effects of factors on the causal effects between SES and AD.

Results: As indicated by the results of the IVW model, educational years (OR = 0.708, 95% CI 0.610-0.821, P < 0.001) and household income (OR = 0.746, 95% CI 0.566-0.982, P = 0.037) was associated with a decreased genetic susceptibility risk for AD. The univariable results showed that the causal effect of educational years on the lower risk of AD remained significant (OR = 0.643, 95% CI 0.467-0.886, P = 0.006). In addition, our findings indicated that C-reactive protein (CRP) played a role in the causal effect of educational years on AD. The proportions of mediation were - 50.08% (95% CI - 92.78; - 7.38%).

Discussion: These findings provided evidence supporting the causal effect of educational attainment lower AD risk, with inflammation playing a mediating role. These findings may inform prevention strategies and interventions directed toward AD. Future studies should explore other plausible biological mechanisms.