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While studies have linked PM\n                    <jats:sub>2.5<\/jats:sub>\n                    exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM\n                    <jats:sub>2.5<\/jats:sub>\n                    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 A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM\n                    <jats:sub>2.5<\/jats:sub>\n                    exposure for the year preceding participants\u2019 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\n                    <jats:sub>2.5<\/jats:sub>\n                    and decreased CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from \u22120.015\u2013\u22120.029 per 1 ug\/m\n                    <jats:sup>3<\/jats:sup>\n                    increase in PM\n                    <jats:sub>2.5<\/jats:sub>\n                    exposure. The proportion mediated ranging from 14\u201343%. 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\n                    <jats:sub>2.5<\/jats:sub>\n                    exposure and CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM\n                    <jats:sub>2.5<\/jats:sub>\n                    toxicity in the pre-clinical stages of AD.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03662-9","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T03:35:27Z","timestamp":1781062527000},"page":"5811-5822","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer\u2019s disease among a cognitively normal population-based cohort"],"prefix":"10.1038","volume":"31","author":[{"given":"Tszshan","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7311-2298","authenticated-orcid":false,"given":"Donghai","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Ebelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Steenland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3153-502X","authenticated-orcid":false,"given":"Allan I.","family":"Levey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8810-620X","authenticated-orcid":false,"given":"James J.","family":"Lah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliza P.","family":"Wingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-6282","authenticated-orcid":false,"given":"Thomas S.","family":"Wingo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6005-417X","authenticated-orcid":false,"given":"Anke","family":"H\u00fcls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"3662_CR1","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1002\/alz.13016","volume":"19","author":"MA Better","year":"2023","unstructured":"Better MA. 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