INTRODUCTION:Growing evidence indicates fine particulate matter (PM2.5) as risk factor for Alzheimer’s’ disease (AD), but the underlying mechanisms have been insufficiently investigated. We hypothesized differential DNA methylation (DNAm) in brain tissue as potential mediator of this association.METHODS:We assessed genome-wide DNAm (Illumina EPIC BeadChips) in prefrontal cortex tissue and three AD-related neuropathological markers (Braak stage, CERAD, ABC score) for 159 donors, and estimated donors’ residential traffic-related PM2.5exposure 1, 3 and 5 years prior to death. We used a combination of the Meet-in-the-Middle approach, high-dimensional mediation analysis, and causal mediation analysis to identify potential mediating CpGs.RESULTS:PM2.5was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-six CpG sites were identified as mediators of the association between PM2.5exposure and neuropathology markers, several located in genes related to neuroinflammation.DISCUSSION:Our findings suggest differential DNAm related to neuroinflammation mediates the association between traffic-related PM2.5and AD.