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We assembled a unified single-nucleus atlas from 867 diverse brains. Meta-analysis identified new cell-state associations with AD and prioritized a non-canonical reactive\n                  <jats:italic>\n                    SLC38A2\n                    <jats:sup>high<\/jats:sup>\n                    SMTN\n                    <jats:sup>high<\/jats:sup>\n                    CACNA1D\n                    <jats:sup>high<\/jats:sup>\n                  <\/jats:italic>\n                  astrocyte (Ast10) as a key link between neuropathologies and cognitive decline. To identify regulators of Ast10 emergence, we modeled ligand-receptor relationships. Independent datasets and two spatial modalities validated these drivers and revealed Ast10\u2019s multifocal distribution throughout the neocortex. Mechanistic validation in mouse and human astrocytes confirmed\n                  <jats:italic>PLXNB1<\/jats:italic>\n                  ,\n                  <jats:italic>JAM2<\/jats:italic>\n                  and\n                  <jats:italic>SEMA4D<\/jats:italic>\n                  as regulators. In cerebrospinal fluid from a SEMA4D-blocking antibody trial, Ast10 markers are pharmacologically modifiable, and their reduction tracks with cognitive stabilization. Ast10 may contribute to cognitive decline through disrupted presynaptic neurotransmitter release and may be a convergence point for AD and other neurodegenerative pathologies, a promising target for enhancing resilience to dementia.\n                <\/jats:p>","DOI":"10.1101\/2025.02.24.639868","type":"posted-content","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T17:36:22Z","timestamp":1740504982000},"source":"Crossref","is-referenced-by-count":15,"title":["A systems approach uncovers drivers of the multifocal emergence of an astrocyte state contributing to cognitive decline in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7981-7333","authenticated-orcid":false,"given":"Natacha","family":"Comandante-Lou","sequence":"first","affiliation":[{"name":"Center for Translational and Computational Neuroimmunology, Columbia University Irving Medical Center, Department of Neurology and the Taub Institute for the Study of 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