{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T08:19:24Z","timestamp":1766132364342,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,16]]},"group-title":"Pathology","reference-count":89,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Some individuals are capable of tolerating Alzheimer disease neuropathological changes (ADNC) without manifesting clinical symptoms. Elucidating the neuropathological, and molecular mediators may facilitate the identification of more accurate\n                    <jats:italic>in vivo<\/jats:italic>\n                    biomarkers and inform the development of targeted therapeutic strategies.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To investigate cellular distribution of tau pathology, microglial responses, and gene expression profiles associated with divergent clinical outcomes (dementia vs. no dementia) in individuals exhibiting comparable ADNC.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design, Setting and Participants<\/jats:title>\n                  <jats:p>We analyzed postmortem brain tissue from 97 participants from the ROSMAP study:49 with high likelihood of AD (25 demented [demented AD] and 24 cognitively normal [resilient]), and 48 with low likelihood (22 demented [impaired-other (IMP-O)] and 26 cognitively normal [control]). Cases were matched for age, gender, and co-pathologies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main outcomes and measures<\/jats:title>\n                  <jats:p>Amyloid-\u03b2 plaques, phospho-tau pathology (tangles and tau-positive neurites), tau oligomers in synaptic-fractions, tau seeding activity, neurons, synapse density, and astrocyte and microglia activation were quantified. The relationships with bulk and microglia-specific RNA-sequencing were also examined. Statistical analyses employed ANOVA with Tukey\u2019s HSD\/Bonferroni corrections for pathological and clinical variables, and the Wald test for differential gene expression<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Demented AD and resilient brains exhibited comparable tau tangle and amyloid-\u03b2 plaques; however, demented AD showed higher total pTau burden (tangles and tau-positive neurites) (Mean[SD], 27.39%[21.89%] vs. 10.60%[14.71%]; p= 0.0004) and elevated pTau oligomer levels in synaptic-enriched fractions (0.48[0.52] vs. 0.16[0.19]; p=0.0010). Both demented AD (0.21\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    [0.14\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    ]; p&lt;0.0001) and IMP-O (0.62\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    [0.42\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    ]; p&lt;0.0001) showed greater synaptic loss than resilient (1.54\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    [0.55\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    ]; p=0.0008) and controls (2.92\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    [1.13\u00d710\n                    <jats:sup>7<\/jats:sup>\n                    ]). CD68+ microglia burden was increased in demented (1.14%[0.27%]; p&lt;0.0001) and IMP-O (0.97%[0.36%]; p&lt;0.0001) but not in resilient (0.72% [0.17%]; p=0.2835) compared to controls (0.59%[0.17%]). Synaptic pTau oligomers and CD68+ microglia were the strongest correlates with antemortem cognition. Resilient brains exhibited downregulation of neuroinflammation-related genes and possessed a distinct microglial subpopulation supporting resilience, characterized by overexpression of CD83, DUSP1, and NAMPT.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion and relevance<\/jats:title>\n                  <jats:p>Our findings suggest that aberrant accumulation of tau in neurites and synapses, rather than tangles within neuronal soma, may trigger a microglial pro-inflammatory activation linked to synaptic loss and impaired cognition. Cell-specific transcriptomic analysis identified a distinct microglial cell subpopulation associated with resilience to ADNC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.15.25341752","type":"posted-content","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T20:05:20Z","timestamp":1765915520000},"source":"Crossref","is-referenced-by-count":0,"title":["Neuronal Distribution of Tau Pathology, Microglial Gene Expression Trajectories, and Resilience to Alzheimer disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6217-2348","authenticated-orcid":false,"given":"Sunny","family":"Kumar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana 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