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

Cite

Lee, D., Vicari, J.M., Porras, C., Spencer, C., Pjanic, M., Wang, X., Kinrot, S., Weiler, P., Kosoy, R., Bendl, J. and Prashant, N.M., 2024. Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease. Nat Genet (2026).

https://doi.org/10.1038/s41588-026-02716-6

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.

Datasets

1. Fresh ex vivo myeloid single cell RNA-seq from human prefrontal cortex

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CERAD
Braak
Dementia
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Reference genome
FM_22538,337 cells
FM_29227,098 cells
FM_24319,262 cells
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FM_161739 cells
FM_044676 cells
FM_164405 cells
FM_031370 cells
FM_279303 cells
FM_069257 cells
FM_070251 cells
FM_304152 cells
Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease

2. Frozen in silico sorted myeloid single nuclei RNA-seq from human prefrontal cortex

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Rep ID
Pool ID
Sample source
Cell type
Cell type (subclass)
Cell sub type
Assay
Disease
Sex
Tissue
Ethnicity
Age
Age group
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Reference genome
Rep 1144,577 cells
Rep 2144,127 cells
Rep 4405 cells
Rep 3384 cells
Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease

Alias names

syn52795287, PsychAD