Plate IV.18 · Publications
Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease
Article in Nature Genetics, 11 August 2026.
Abstract
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.
Versions2
- PublishedNature Genetics10.1038/s41588-026-02716-6
- PreprintmedRxiv10.1101/2023.10.25.23297558
Cite
@article{lee2026plasticity,
title = {{Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease}},
author = {Lee, Donghoon and Vicari, James M. and Porras, Christian and Spencer, Collin and Pjanic, Milos and Wang, Xinyi and Kinrot, Seon and Weiler, Philipp and Kosoy, Roman and Bendl, Jaroslav and N M, Prashant and Psychogyiou, Konstantina and Malakates, Periklis and Hennigan, Evelyn and Monteiro Fortes, Jennifer and Zheng, Shiwei and Therrien, Karen and Mathur, Deepika and Kleopoulos, Steven P. and Shao, Zhiping and Argyriou, Stathis and Alvia, Marcela and Casey, Clara and Hong, Aram and Beaumont, Kristin G. and Sebra, Robert and Kellner, Christopher P. and Bennett, David A. and Yuan, Guo-Cheng and Voloudakis, Georgios and Theis, Fabian J. and Haroutunian, Vahram and Hoffman, Gabriel E. and Fullard, John F. and Roussos, Panos},
journal = {Nature Genetics},
publisher = {Springer Science and Business Media LLC},
year = {2026},
month = aug,
doi = {10.1038/s41588-026-02716-6},
url = {https://doi.org/10.1038/s41588-026-02716-6},
pmid = {42581323}
}