{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:52:03Z","timestamp":1793908323826,"version":"4.8.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG17917"],"award-info":[{"award-number":["R01AG17917"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG054617"],"award-info":[{"award-number":["RF1AG054617"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG000247"],"award-info":[{"award-number":["T32AG000247"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG072475"],"award-info":[{"award-number":["R01AG072475"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007707","name":"University of California, Davis","doi-asserted-by":"publisher","award":["R13 AG030995"],"award-info":[{"award-number":["R13 AG030995"]}],"id":[{"id":"10.13039\/100007707","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Females show a disproportionate burden of Alzheimer\u2019s disease pathology and higher Alzheimer\u2019s disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer\u2019s disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex.<\/jats:p>\n               <jats:p>187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-\u03b2 and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-\u03b2 and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-\u03b2 to tau relationship in the whole sample and stratified by sex (amyloid-\u03b2 \u2192 microglial activation \u2192 tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation \u2192 amyloid-\u03b2 \u2192 tau).<\/jats:p>\n               <jats:p>Microglial activation significantly mediated 33% [95% confidence interval (CI) 10\u201367] of the relationship between amyloid-\u03b2 and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22\u2013100) of the effect of amyloid-\u03b2 on tau was mediated through microglial activation in females, compared to 19% (95% CI 0\u201364) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-\u03b2 to tau relationship (mediational effect: 50%, 95% CI 23\u201390) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10\u201377). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32\u2013100) (mediational effect: 26%, 95% CI 0\u201368).<\/jats:p>\n               <jats:p>Our models suggest a reciprocal, bidirectional relationship between amyloid-\u03b2 and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-\u03b2 with tau were observed. Microglial activation may be disproportionately important for Alzheimer\u2019s disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer\u2019s disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.<\/jats:p>","DOI":"10.1093\/brain\/awac257","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T05:09:36Z","timestamp":1658552976000},"page":"3536-3545","source":"Crossref","is-referenced-by-count":88,"title":["Sex-specific effects of microglial activation on Alzheimer\u2019s disease proteinopathy in older adults"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0610-6933","authenticated-orcid":false,"given":"Kaitlin B","family":"Casaletto","sequence":"first","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California , San Francisco, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahan","family":"Aslanyan","sequence":"additional","affiliation":[{"name":"Mark and Mary Stevens Neuroimaging and Informatics Institute, Department of Neurology, University of Southern California , Los Angeles, CA , USA"},{"name":"Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California , Los Angeles, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M","family":"Simone","sequence":"additional","affiliation":[{"name":"Temple University, Department of Psychology , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-2221","authenticated-orcid":false,"given":"Jennifer S","family":"Rabin","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto , Toronto, ON , Canada"},{"name":"Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Research Institute , Toronto, ON , Canada"},{"name":"Rehabilitation Sciences Institute, University of Toronto , Toronto, ON , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-8100","authenticated-orcid":false,"given":"Renaud","family":"La Joie","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California , San Francisco, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M","family":"Brickman","sequence":"additional","affiliation":[{"name":"Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Dams-O\u2019Connor","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai , New York, NY , USA"},{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Palta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of General Medicine, Columbia University Irving Medical Center , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj G","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8773-7678","authenticated-orcid":false,"given":"Kristen M","family":"George","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, University of California Davis School of Medicine , Davis, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L","family":"Satizabal","sequence":"additional","affiliation":[{"name":"Department of Population Health Science and Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, UT Health San Antonio , San Antonio, TX , USA"},{"name":"Department of Neurology, Boston University School of Medicine , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University , Chicago, IL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Pa","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Alzheimer\u2019s Disease Cooperative Study (ADCS), University of California , San Diego, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"2023060106301193000_awac257-B1","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.jalz.2018.04.008","article-title":"Understanding the impact of sex and gender in Alzheimer\u2019s disease: A call to action","volume":"14","author":"Nebel","year":"2018","journal-title":"Alzheimer\u2019s 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