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While female sex and\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study\/Memory and Aging Project (ROS\/MAP;\n                    <jats:italic>n<\/jats:italic>\n                    =1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-\u03b2 burden were used to determine the extent to which amyloid-\u03b2 pathology mediated associations of\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    carriership and sex with MTL tau burden. In both cohorts,\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    carriership and female sex were associated with significantly greater MTL tau pathology (all\n                    <jats:italic>p<\/jats:italic>\n                    &lt;0.001). Adjustment for global amyloid-\u03b2 attenuated but did not eliminate these associations (\n                    <jats:italic>p<\/jats:italic>\n                    \u22640.024). However, after jointly accounting for global and MTL amyloid-\u03b2 burden, the association between\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    and MTL tau was no longer significant in either cohort (\n                    <jats:italic>p<\/jats:italic>\n                    \u22650.19), whereas the association between female sex and MTL tau remained robust (\n                    <jats:italic>p<\/jats:italic>\n                    \u22640.004). Models incorporating both global and regional MTL amyloid-\u03b2 explained substantially more variance in MTL tau burden than models including only global amyloid-\u03b2, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-\u03b2 to the APOE-\u03b54-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03095-2","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:25:20Z","timestamp":1791537920000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Global and regional amyloid-\u03b2 in explaining APOE-\u03b54 and sex associations with medial temporal tau: a neuropathology study"],"prefix":"10.1007","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-9230","authenticated-orcid":false,"given":"Gemma","family":"Salvad\u00f3","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Groot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Wisse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob W.","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Reiman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"3095_CR1","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1002\/ana.24135","volume":"75","author":"A Altmann","year":"2014","unstructured":"Altmann A, Tian L, Henderson VW, Greicius MD (2014) Sex modifies the APOE-related risk of developing Alzheimer disease. 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