Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort
Ma, T.; Liu, J.; Liang, D.; Ebelt, S.; Steenland, K.; I. Levey, A.; J. Lah, J.; P. Wingo, A.; S. Wingo, T.; Huels, A.
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IntroductionFine particulate matter (PM2.5) is a known risk factor for Alzheimers disease (AD), with emerging evidence linking PM2.5 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. MethodsIn 535 cognitively normal individuals, we assessed genome-wide blood DNAm, CSF A{beta}42 concentrations, and residential PM2.5 exposure in the year preceding blood collection. Multi-stage comprehensive mediation analyses were conducted. ResultsNine CpG sites mediated the PM2.5-A{beta}42 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/m3 increase in PM2.5 exposure. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. DiscussionOur findings suggest that differential DNAm, particularly in neuroinflammation-related genes, mediates PM2.5 toxicity in ADs pre-clinical stage.
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