Background Alzheimer’s disease (AD) imposes a substantial public health burden, and socioeconomic status, particularly household income, has been implicated as a key determinant of disease risk. However, the causal nature of this relationship and the mediating mechanisms remain incompletely characterized.
Methods A bidirectional, two‑sample, two‑stage Mendelian randomization (MR) study was conducted using summary-level data from large-scale genome-wide association studies. Genetic instruments for household income (n = 397,751), cognitive performance (n = 257,841), and AD (21,982 cases and 41,944 controls) were extracted. Inverse variance weighted (IVW), MR‑Egger, weighted median, and MR‑PRESSO methods were applied. Mediation analysis was employed to decompose the total effect into direct and indirect (via cognitive performance) components. Robustness was assessed through sensitivity analyses and reverse-direction MR.
Results Genetically predicted higher household income was associated with a protective effect on AD risk (IVW OR = 0.79, 95% CI: 0.68–0.92). Cognitive performance mediated 65.7% of this total effect. No reverse causal effect of AD on household income was observed. Sensitivity analyses confirmed the robustness of these findings.
Conclusions Household income exerts a protective causal effect on AD, which is predominantly mediated by cognitive performance. These results elucidate a key mechanistic pathway linking socioeconomic factors to neurodegenerative disease and highlight cognitive function as a potential interventional target, supporting the integration of socioeconomic considerations into AD prevention strategies.
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Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare
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