Causal associations between socioeconomic status and Alzheimer’s disease: a Mendelian randomization and Mediation Analysis

Abstract Background and Objectives: Observational studies have shown that socio-economic status (SES) is strongly associated with Alzheimer’s disease (AD). However, the biological mechanisms underpinning this association remain unclear. Therefore, using a Mendelian Randomization (MR) approach, the aim was to explore the causal relationship between SES and genetic susceptibility to dementia. 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. 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). Additionally, 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: This MR study provided evidence supporting the causal effect of educational attainment lower AD risk, with CRP playing a mediating role. These findings may inform prevention strategies and interventions directed toward AD.