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Variants within the\n                    <jats:italic>MS4A<\/jats:italic>\n                    locus are strongly associated with AD risk and resilience and are linked to microglial biology; however, the functional role of\n                    <jats:italic>MS4A4A<\/jats:italic>\n                    in plaque-associated tau pathology remains poorly understood.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    Single-nucleus RNA sequencing (snRNA-seq) was performed on hippocampi from non-transgenic,\n                    <jats:italic>Ms4a4a<\/jats:italic>\n                    knockout (4A-KO), 5xFAD, and 5xFAD 4A-KO mice at 6 months of age. To assess plaque-associated tau pathology, AD-derived tau aggregates were injected into the hippocampus of 5xFAD and 5xFAD 4A-KO mice at 6 months, and histological analyses were performed 3 months later.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    Amyloid pathology was the dominant driver of microglial state transitions, while\n                    <jats:italic>Ms4a4a<\/jats:italic>\n                    loss selectively remodeled activated microglial transcriptional programs enriched for interferon, lysosomal, autophagic, and proteostatic pathways. Activated microglia from 5xFAD 4A-KO mice exhibited altered expression of genes linked to immune signaling and protein handling. Following AD-tau inoculation,\n                    <jats:italic>Ms4a4a<\/jats:italic>\n                    loss did not significantly alter overall phospho-tau burden but selectively reduced dense-core plaque-associated neuritic plaque tau (NP-tau), particularly in the contralateral hemisphere. This phenotype was strongest surrounding X-34-positive fibrillar plaques and occurred without major changes in plaque-associated microgliosis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>\n                    These findings identify\n                    <jats:italic>Ms4a4a<\/jats:italic>\n                    as a regulator of plaque-associated microglial programs linked to NP-tau accumulation in the amyloid-bearing brain. More broadly, this work supports a model in which AD resilience-associated microglial pathways selectively shape plaque-associated microenvironments that promote downstream tau pathology.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.22.740167","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T18:00:22Z","timestamp":1785175222000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Ms4a4a<\/i>\n                  loss reprograms amyloid-associated microglia and limits dense-core plaque-associated tau spreading"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0737-9311","authenticated-orcid":false,"given":"Emma P.","family":"Danhash","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Washington University in St. Louis School of 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