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Previous epigenome-wide association studies using 450K arrays captured limited CpG coverage and often focused on a single neuropathological measure. Here we profiled DNAm in 1,250 postmortem prefrontal cortex samples from the Rush Alzheimer\u2019s Disease cohorts using the Infinium MethylationEPIC v2 array (~930,000 CpGs) and performed epigenome-wide association studies of multiple neuropathologic measures, including AD diagnosis, amyloid-\u03b2 and tau tangles. We identified 107 differentially methylated probes associated with AD neuropathology, 38 of which were replicated in an independent cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009139). DNAm also partially mediated the effect of\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype on AD diagnosis (proportion mediated: 8.6%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20092\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    ). Moreover, 39 identified genes (for example,\n                    <jats:italic>RIN3<\/jats:italic>\n                    ,\n                    <jats:italic>LGMN<\/jats:italic>\n                    ,\n                    <jats:italic>LHPP<\/jats:italic>\n                    ) were differentially expressed across major brain cell types, including neurons and astrocytes. These findings expand the epigenetic landscape of AD neuropathology and reveal DNAm as a mediator of\n                    <jats:italic>APOE<\/jats:italic>\n                    -related genetic risk.\n                  <\/jats:p>","DOI":"10.1038\/s43587-026-01243-7","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:54:07Z","timestamp":1791820447000},"page":"2493-2503","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain DNA methylation, APOE genotype and Alzheimer\u2019s disease neuropathology in a large postmortem cohort"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8083-7032","authenticated-orcid":false,"given":"Guanhong","family":"Miao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0237-8758","authenticated-orcid":false,"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-4189","authenticated-orcid":false,"given":"Yun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francine","family":"Grodstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-1752","authenticated-orcid":false,"given":"Julie A.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa L.","family":"Barnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3205-8130","authenticated-orcid":false,"given":"Bing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3243-2660","authenticated-orcid":false,"given":"Jinying","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"1243_CR1","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrg3354","volume":"14","author":"ZD Smith","year":"2013","unstructured":"Smith, Z. 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