Differential DNA methylation in blood as potential mediator of the association between ambient PM 2.5 and cerebrospinal fluid biomarkers of Alzheimer’s disease among a cognitively normal population-based cohort

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Introduction Fine particulate matter (PM 2.5 ) is a known risk factor for Alzheimer’s disease (AD), with emerging evidence linking PM 2.5 exposure to cerebrospinal fluid (CSF) biomarkers in pre-clinical stages. However, the role of DNA methylation (DNAm) as potential mediator in this relationship among cognitively normal individuals remains largely unexplored. Methods In 535 cognitively normal individuals, we assessed genome-wide blood DNAm, CSF Aβ 42 concentrations, and residential PM 2.5 exposure in the year preceding blood collection. Multi-stage comprehensive mediation analyses were conducted. Results Nine CpG sites mediated the PM 2.5 –Aβ42 association, with significant natural indirect effects (NIEs) for eight CpGs, mediating 14–43% of the effect. The joint NIE for all nine CpGs was -0.115 (95% CI: -0.215, -0.101) per 1 ug/m 3 increase in PM 2.5 exposure. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. Discussion Our findings suggest that differential DNAm, particularly in neuroinflammation-related genes, mediates PM 2.5 toxicity in AD’s pre-clinical stage.