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

Abstract 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 Aβ 42 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 Aβ 42 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/m 3 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 Aβ 42 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.