Differential DNA Methylation in the Brain as Potential Mediator of the Association between Traffic-related PM2.5 and Neuropathology Markers of Alzheimer's Disease

Zhenjiang Li; Donghai Liang; Stefanie Ebelt; Marla Gearing; Michael S Kobor; Chaini Konwar; Julie L Maclsaac; Kristy Dever; Aliza Wingo; Allan Levey; James J Lah; Thomas Wingo; Anke Huels

doi:10.1101/2023.06.30.23292085

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

medRxiv [Preprint]. 2023 Jun 30:2023.06.30.23292085. doi: 10.1101/2023.06.30.23292085.

Authors

Zhenjiang Li¹, Donghai Liang^{1

2}, Stefanie Ebelt^{1

2}, Marla Gearing^{3

4}, Michael S Kobor^{5

6

7}, Chaini Konwar^{5

6}, Julie L Maclsaac^{5

6

7}, Kristy Dever^{5

6

7}, Aliza Wingo^{8

9}, Allan Levey⁴, James J Lah⁴, Thomas Wingo^{4

10}, Anke Huels^{1

2}

Affiliations

¹ Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Atlanta, GA 30322, USA.
² Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Atlanta, GA 30322, USA.
³ Department of Pathology and Laboratory Medicine, Emory University, 1364 Clifton Rd, Atlanta, GA 30322, USA.
⁴ Department of Neurology, Emory University School of Medicine, 12 Executive Park Dr NE, Atlanta, GA 30322, USA.
⁵ Department of Medical Genetics, University of British Columbia, 4500 Oak St, Vancouver, BC V6H 3N1, Canada.
⁶ BC Children's Hospital Research Institute, 938 W 28th Ave, Vancouver, BC V5Z 4H4, Canada.
⁷ Centre for Molecular Medicine and Therapeutics, 950 W 28th Ave, Vancouver, BC V6H 0B3, Canada.
⁸ Division of Mental Health, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA.
⁹ Department of Psychiatry, Emory University School of Medicine, 12 Executive Park Dr NE #200, Atlanta, GA 30329, USA.
¹⁰ Department of Human Genetics, Emory University, 615 Michael Street Suite 301, Atlanta, GA 30322, USA.

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.

Keywords: Alzheimer’s disease; DNA methylation; Traffic-related fine particulate matter; neuropathology.

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Abstract

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