Differential DNA Methylation in the Brain as Potential Mediator of the Association between Traffic-related PM 2.5 and Neuropathology Markers of Alzheimer's Disease.

• Type of Material: Article
• Authors: Zhenjiang Li, Emory University; Donghai Liang, Emory University; Stefanie Ebelt, Emory University; Marla Gearing, Emory University; Michael S Kobor, University of British Columbia; Chaini Konwar, University of British Columbia; Julie L Maclsaac, University of British Columbia; Kristy Dever, University of British Columbia; Aliza Wingo, Emory University; Allan Levey, Emory University; James Lah, Emory University; Thomas Wingo, Emory University; Anke Huels, Emory University
• Language: English
• Date: 2023-06-30
• Publisher: BMJ
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.06.30.23292085
• Title of Journal or Parent Work: medRxiv
• Grant/Funding Information: This work was supported by the HERCULES Pilot Project via NIEHS P30ES019776 (Huels), the Goizueta Alzheimer’s Disease Research Center: Pilot Grant via NIA P50AG025688 (Huels/Liang), the Rollins School of Public Health Dean’s Pilot and Innovation Grant (Huels), NIA R01AG079170 (Huels/Wingo). The air pollution exposure assessment was supported by the NIH grant R21ES032117 (Liang).
• Keywords: Alzheimer’s disease; Traffic-related fine particulate matter; neuropathology; DNA methylation
• Research Categories: Environmental Sciences; Health Sciences, Pathology; Health Sciences, Public Health; Biology, Genetics; Biology, Neuroscience

Abstract

INTRODUCTION: Growing evidence indicates fine particulate matter (PM 2.5 ) 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 PM 2.5 exposure 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: PM 2.5 was significantly associated with differential DNAm at cg25433380 and cg10495669. Twenty-six CpG sites were identified as mediators of the association between PM 2.5 exposure 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 PM 2.5 and AD.