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Lee, D.* ; Vicari, J.M.* ; Porras, C.* ; Spencer, C.* ; Pjanic, M.* ; Wang, X.* ; Kinrot, S.* ; Weiler, P. ; Kosoy, R.* ; Bendl, J.* ; N M, P.* ; Psychogyiou, K.* ; Malakates, P.* ; Hennigan, E.* ; Monteiro Fortes, J.* ; Zheng, S.* ; Therrien, K.* ; Mathur, D.* ; Kleopoulos, S.P.* ; Shao, Z.* ; Argyriou, S.* ; Alvia, M.* ; Casey, C.* ; Hong, A.* ; Beaumont, K.G.* ; Sebra, R.* ; Kellner, C.P.* ; Bennett, D.A.* ; Yuan, G.C.* ; Voloudakis, G.* ; Theis, F.J. ; Haroutunian, V.* ; Hoffman, G.E.* ; Fullard, J.F.* ; Roussos, P.*

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Nat. Genet., DOI: 10.1038/s41588-026-02716-6 (2026)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Single-cell; Inflammatory Macrophages; Cognitive Impairment; Mouse; Pathology; Neuropathology; Expression; Melanoma; States; Gpnmb
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)