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

Fine particulate matter (PM_2.5) is a known risk factor for Alzheimer’s disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM_2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM_2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF Aβ₄₂ concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM_2.5 exposure for the year preceding participants’ blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM_2.5 and decreased CSF Aβ₄₂ concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from −0.015–−0.029 per 1 ug/m³ increase in PM_2.5 exposure. The proportion mediated ranging from 14–43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM_2.5 exposure and CSF Aβ₄₂ concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM_2.5 toxicity in the pre-clinical stages of AD.