Causal relationship of genetically predicted particulate matter 2.5 level with Alzheimer’s disease and the mediating effect of dehydroepiandrosterone sulphate

Abstract

Background: The causal association between particulate matter 2.5 (PM2.5) and Alzheimer’s disease (AD) remains inconclusive, and the mediators of the association have yet to be explored. Aims: We aimed to assess the potential causal relationship between PM2.5 and AD, and to investigate the mediating role of dehydroepiandrosterone sulphate (DHEAS). Subjects and methods: We implemented a two-sample Mendelian randomisation (MR) study to examine the genetic predisposition to PM2.5 exposure and its association with AD. The inverse-variance weighted (IVW) method served as the primary analytical tool to estimate the odds ratio (OR) and 95% confidence interval (95% CI). Results: There were 6 and 4 genetic variants associated with DHEAS and PM2.5, respectively. Based on the multivariable MR analysis, we found that after adjusting for DHEAS, each standard deviation increase in PM2.5 was associated with the risk of AD (OR: 2.96, 95% CI: 1.33, 6.58, p = 0.00769). The MR Egger intercept test did not detect horizontal pleiotropy for PM2.5 (P-pleiotropy = 0.879) and DHEAS(P-pleiotropy = 0.941). According to the results of the mediation analysis, DHEAS accounted for 18.3% of the association between PM2.5 and AD. Conclusion: Our findings affirm a significant causal association between PM2.5 exposure and AD, with DHEAS playing a mediating role in this relationship.