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

AI Summary

PM2.5 exposure associated with decreased CSF Aβ42 in cognitively normal individuals, indicating pre-clinical Alzheimer's disease-related effects.
Nine blood CpGs were identified as mediators; eight showed significant natural indirect effects with proportions mediated ranging 14 to 43 per cent.
Six CpGs annotated to genes implicated in neuroinflammatory pathways, suggesting blood DNA methylation mediates PM2.5 effects on pre-clinical Alzheimer's disease biomarkers.

TL;DR (AI Generated)

Fine particulate matter (PM2.5) 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 PM2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce.

These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM2.5 exposure and CSF Aβ42 concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM2.5 toxicity in the pre-clinical stages of AD.

Basic summary

Mol Psychiatry. 2026 Jun 10. doi: 10.1038/s41380-026-03662-9. Online ahead of print.

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 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.