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Cited by 14Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

The gain-of-function TREM2-T96K mutation increases risk for Alzheimer’s disease by impairing microglial function

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Pilat, Dominika J., Le, Hoang, Prokopenko, Dmitry, Lin, Chih-Chung Jerry, Eimer, William A., Quinti, Luisa, Gavrilles, Evan P., Garcia, Sheyla N. +6 more·2026·Neuron
DOI 10.1016/j.neuron.2025.09.032PMC PMC12687738
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Abstract

We previously reported that T96K is a gain-of-function mutation in TREM2 based on its ability to increase ligand-dependent activation. Here, we show that TREM2 T96K increases risk for Alzheimer's disease (AD) in a whole-genome sequencing dataset comprised of family-based and case-control samples. Trem2 T96K also reduced clustering of microglia around β-amyloid (Aβ) plaques exclusively in female 5xFAD mice. Furthermore, T96K decreased levels of soluble Trem2 in female 5xFAD mice and human microglial cell cultures. We also observed impaired uptake of Aβ in Trem2 T96K knockin microglial cells. Moreover, Trem2 T96K reduced total area of phagocytic microglia, specifically in female 5xFAD mice. Single-cell RNA sequencing (scRNA-seq) profiling of microglia revealed that Trem2 T96K impairs the transition of homeostatic microglia into disease-associated microglia (DAM) in female 5xFAD mice. Downregulated inflammatory pathways associated with Trem2 T96K included interleukin (IL)-6/JAK/STAT3, complement, and interferon (IFN)-γ response. Collectively, our results indicate that, like the loss-of-function mutation R47H, Trem2 T96K adversely affects microglial function in a sex-dependent manner.

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  • The APP/PS1 and 5×FAD models have limitations in recapitulating the slow, age-dependent progression of human AD.

    “although the APP/PS1 and 5×FAD models are valuable for studying amyloid‐driven mechanisms, 43 , 44 , 45 they have limitations in recapitulating the slow, age‐dependent progression of human AD.”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [43]

    The Discussion (page unavailable) describes fast Aβ accumulation in 5xFAD mice and suggests it could create a ceiling effect, supporting a limitation of that model. It does not discuss the APP/PS1 model separately or explicitly compare either model’s progression with slow, age-dependent human AD. (LLM, conf=0.83)

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Sorted by citations

Authors
Pilat, D. J., Le, H., Prokopenko, D., Lin, C.-C. J., Eimer, W. A., Quinti, L., Gavrilles, E. P., Garcia, S. N., Heitman, S. N., McGinty, D., Cetinbas, M., Sadreyev, R. I., Tanzi, R. E., & Griciuc, A.
Affiliations
Harvard University (US)
Corresponding author
  • Tanzi, Rudolph E.
  • Griciuc, Ana
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2026-01
Volume
114
Issue
1
Pages
46-66.e13
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2025.09.032
PMC
PMC12687738
OpenAlex
W4415291920
Cited by
14
References
23
Citations by year
2026: 12 · 2025: 2
FWCI
4.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
  • Harvard University (NG00067.v9)
  • BrightFocus Foundation (A2022009F)
  • JPB Foundation
  • University of Pennsylvania (U24-AG041689)
  • Cure Alzheimer&apos;s Fund
  • National Institute on Aging (R01AG073292)
  • Freedom Together Foundation
  • National Institutes of Health
  • Coins for Alzheimer&apos;s Research Trust
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 › Inflammasome and immune disorders
Keywords
TREM2, gain-of-function mutations, Alzheimer's disease risk, microglial function, sex effects, neuroinflammation
MeSH terms
Gain of Function Mutation, Alzheimer Disease, Animals, Female, Humans, Male, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Genetic Predisposition to Disease, Mice, Plaque, Amyloid

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