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Cited by 132Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsSingle-cell and spatial transcriptomics

An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains

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Millet, Alon, Ledo, Jose Henrique, Tavazoie, Sohail F.·2024·Immunity
DOI 10.1016/j.immuni.2023.12.001PMC PMC10805152
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Abstract

The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.

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  • A longitudinal single-cell RNAseq atlas defined DAM states as a transitional profile leading to a terminally inflammatory microglia (TIM) state, enriched in stress and inflammatory genes and devoid of homeostatic gene expression.

    “More recently, a longitudinal single-cell RNAseq atlas of microglial cells during experimental AD has defined DAM states as a transitional profile that ultimately leads to a terminally inflammatory microglia (TIM) state, which is enriched in stress and inflammatory genes, and is devoid of homeostatic genes expression [38].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [38]

    In Results, the single-cell RNA-sequencing section reports a modeled flow from homeostatic microglia through inflammatory clusters to TIMs; the Discussion describes TIMs as expressing inflammatory markers and stress signatures. The passages do not identify DAMs specifically as the transitional stage or establish that TIMs lack all homeostatic gene expression. The Results also describe TIMs as less inflammatory than DAMs in their predicted cell interactions. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TIM are detected in human AD single nucleus RNAseq datasets, suggesting similar patterns of microglia transcriptional states exist in AD.

    “Remarkably, TIM are also detected in human AD single nucleus RNAseq datasets, suggesting that similar patterns of microglia transcriptional states exist in AD [38].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [38]

  • TIM express several markers of exhausted cells and have an altered capability to phagocytose Aβ.

    “Functional ex vivo studies on TIM indicate they express several markers of exhausted cells and have an altered capability to phagocytose A β .”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [38]

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Cited by

Sorted by citations

Authors
Millet, A., Ledo, J. H., & Tavazoie, S. F.
Affiliations
Rockefeller University (US)
Corresponding author
Tavazoie, Sohail F.
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2024-01
Volume
57
Issue
1
Pages
153-170.e6
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2023.12.001
PMC
PMC10805152
OpenAlex
W4390399168
Cited by
132
References
43
Citations by year
2026: 68 · 2025: 45 · 2024: 19
FWCI
13.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (T32 GM132083)
  • Medical University of South Carolina
  • Rockefeller University
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
Alzheimer's disease, microglia, APOE ε4, aging, neuroinflammation, amyloid-beta clearance, aducanumab, single-cell atlas, chromatin accessibility, intercellular communication, APOE alleles, neuroimmune function
MeSH terms
Aged, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Genotype, Humans, Microglia, Mice, Apolipoprotein E4

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