Summary: Researchers have identified a mutation in the TREM2 gene that interferes with the brain’s ability to clear toxic amyloid plaques and raises risk for Alzheimer’s disease. The mutation, called T96K, is a gain-of-function change that leaves TREM2 chronically overactive. Paradoxically, this overactivity undermines microglial plaque-clearing activity, with especially noticeable effects in female mice in the Alzheimer’s model.
Using genetically engineered mouse models, the team found that microglia carrying the overactive TREM2 variant responded poorly to amyloid accumulation and provided less protection against neurodegeneration. The study shows that both excessive and insufficient TREM2 signaling can damage brain health, a finding that has important implications for designing safer therapies targeting microglial function in Alzheimer’s disease.
Key Facts:
- New mutation identified: The TREM2-T96K gain-of-function mutation reduces microglial capacity to remove amyloid plaques.
- Sex-specific effect: The mutation impaired microglial protection and plaque clearance in female Alzheimer’s model mice.
- Therapeutic implications: Strategies that boost TREM2 activity may not always be protective and could worsen Alzheimer’s pathology if they drive excessive activation.
Source: Mass General
Dominika Pilat, PhD, and Ana Griciuc, PhD, of the Department of Neurology at Massachusetts General Hospital, are lead and senior authors of the paper published in Neuron, “The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer’s Disease by Impairing Microglial Function.”
What the researchers wanted to learn
The investigators aimed to determine how microglia—the brain’s resident immune cells—contribute to Alzheimer’s disease (AD) and how genetic variants in microglial genes influence disease risk. Previous work has linked changes in microglial genes to late-onset AD; this study focused on a specific TREM2 variant to clarify whether increased TREM2 activity helps or harms brain health.
TREM2 acts as a molecular switch that activates microglia to recognize and clear amyloid-beta (Aβ) plaques—abnormal protein deposits that accumulate between neurons in AD. The T96K mutation is classified as gain-of-function because it increases TREM2 activation, keeping the receptor in an abnormally active state.
Approach and methods
To study the T96K mutation, the team combined human genetic analyses with experimental mouse models and cellular assays. They generated a novel TREM2-T96K knock-in mouse and crossed it with an established Alzheimer’s model to produce animals that develop AD-like amyloid pathology. The investigators examined brain tissue using confocal microscopy, quantified proteins with ELISA, and profiled microglia with single-cell RNA sequencing followed by bioinformatic analysis to characterize how the mutation alters microglial states over time.
Key findings
This work is the first to demonstrate that a gain-of-function TREM2 mutation can increase Alzheimer’s risk by impairing microglial function. The T96K variant diminished microglial engagement with amyloid plaques, reduced the overall area covered by microglial processes that normally surround and contain plaques, and suppressed microglia’s disease-response signatures. Importantly, these detrimental effects were most pronounced in female AD-model mice in the study.
Implications for therapy
The findings challenge the assumption that boosting TREM2 activity is universally beneficial. While some TREM2-targeted approaches aim to enhance microglial plaque clearance, this study shows that excessive TREM2 signaling can be counterproductive. Therapeutic strategies should therefore account for the complexity of TREM2 regulation, potential sex-specific responses, and the balance between activating and restraining microglial functions.
Next steps
Future experiments will investigate how TREM2 gain-of-function mutations affect microglial immune responses, lipid metabolism, and cellular aging. These studies will use human microglia-like cells and additional mouse models to deepen understanding of how altered TREM2 signaling contributes to Alzheimer’s pathogenesis and to refine potential treatment strategies.
Authorship: In addition to Pilat and Griciuc, contributors from Mass General Brigham include Hoang Le, Dmitry Prokopenko, Chih-Chung Jerry Lin, William A. Eimer, Luisa Quinti, Evan P. Gavrilles, Sheyla N. Garcia, Sara N. Heitman, Danielle McGinty, Murat Cetinbas, Ruslan I. Sadreyev, and Rudolph E. Tanzi.
Paper cited: Pilat, D.J., et al. “The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer’s Disease by Impairing Microglial Function.” Neuron. DOI: 10.1016/j.neuron.2025.09.032
Funding: This research was supported by grants from the NIA/NIH (R01AG073292 to A.G.), Cure Alzheimer’s Fund (A.G. and R.E.T.), Coins for Alzheimer’s Research Trust Fund (A.G.), Freedom Together Foundation (R.E.T.), BrightFocus Foundation fellowship A2022009F (H.L.), and NIDDK/NIH grant P30DK040561 (R.S.).
Disclosures: The authors report no competing financial or commercial interests. The study received federal and nonprofit funding.
Key Questions Answered:
A: The T96K mutation locks TREM2 in an overactive state, which paradoxically makes microglia less effective at clearing amyloid plaques that drive Alzheimer’s disease.
A: It challenges the prevailing view that increasing TREM2 activity is always protective, showing that excessive activation can be harmful and should be considered when developing therapies.
A: Researchers will explore how TREM2 gain-of-function variants influence microglial metabolism, immune signaling, and cellular aging to inform safer and more targeted AD treatments.
About this genetics and Alzheimer’s disease research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: The image is credited to Neuroscience News
Original Research: The findings will appear in Neuron.