{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T18:19:46Z","timestamp":1788718786046,"version":"build-2803163510"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T00:00:00Z","timestamp":1722816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AG078110"],"award-info":[{"award-number":["T32 AG078110"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AG066865"],"award-info":[{"award-number":["R21 AG066865"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG057187"],"award-info":[{"award-number":["R01 AG057187"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 AG072946"],"award-info":[{"award-number":["P30 AG072946"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1 NS118584"],"award-info":[{"award-number":["RF1 NS118584"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease progression, but details of the disease-driving influence of microglia are poorly understood. Microglial cells can be parsed into subtypes based on their histological appearance. One subtype of microglia, termed dystrophic microglia, is characterized structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-\u03b2 might induce dystrophic changes in microglia, potentially linking amyloid-\u03b2 and tau pathologies to their effects on these microglia.<\/jats:p>\n               <jats:p>We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in Alzheimer's disease progression. We speculated that if their presence is unique to Alzheimer's disease neuropathological change, they would be substantially more common in Alzheimer's disease neuropathological change than in neurodegenerative diseases characterized by other proteinopathies, e.g. \u03b1-synuclein or transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced Alzheimer's disease stages, including comparative conditions such as Lewy body disease and limbic-predominant age-related TDP-43 encephalopathy neuropathological change. Using stereological sampling and digital pathology, we assessed populations of ramified, hypertrophic and dystrophic microglia. We found a significant increase in dystrophic microglia in areas affected early by Alzheimer's disease neuropathological change, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest that dystrophic microglia might impact the regional spread of Alzheimer's disease neuropathological change. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which was then associated with the spread of amyloid-\u03b2 and tau.<\/jats:p>\n               <jats:p>These results suggest that a loss of the protective role of microglia could contribute to the spread of Alzheimer's disease neuropathological change and indicate that further research into preserving microglial function might be warranted.<\/jats:p>","DOI":"10.1093\/brain\/awae258","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T12:01:47Z","timestamp":1722859307000},"page":"89-101","source":"Crossref","is-referenced-by-count":22,"title":["Exploring the link between dystrophic microglia and the spread of Alzheimer's neuropathology"],"prefix":"10.1093","volume":"148","author":[{"given":"Ryan K","family":"Shahidehpour","sequence":"first","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Department of Neuroscience, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T","family":"Nelson","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Department of Neuroscience, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0188-8094","authenticated-orcid":false,"given":"Yuriko","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Department of Biostatistics, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-6757","authenticated-orcid":false,"given":"Adam D","family":"Bachstetter","sequence":"additional","affiliation":[{"name":"Spinal Cord and Brain Injury Research Center, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]},{"name":"Department of Neuroscience, University of Kentucky , Lexington, KY 40536 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,5]]},"reference":[{"key":"2025010718540988100_awae258-B1","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1002\/glia.23046","article-title":"The \u201cBig-Bang\u201d for modern glial 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