Home › Research › Laboratory science
The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function
Pilat DJ, Le H, Prokopenko D, Lin CJ, Eimer WA, Quinti L, Gavrilles EP, Garcia SN, Heitman SN, Alzheimer’s Disease Neuroimaging Initiative (ADNI), McGinty D, Cetinbas M, et al.. Neuron, 2025-10-17
Topic: Brain proteins, microglia and lab models
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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Pilat, D. J., Le, H., Prokopenko, D., Lin, C. J., Eimer, W. A., Quinti, L., et al. (2026). The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function. Neuron. https://doi.org/10.1016/j.neuron.2025.09.032
Vancouver
Pilat DJ, Le H, Prokopenko D, Lin CJ, Eimer WA, Quinti L, et al. The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function. Neuron. 2026. doi:10.1016/j.neuron.2025.09.032. PMID: 41109213.
BibTeX
@article{pilat2026-41109213,
author = {Pilat, D. J. and Le, H. and Prokopenko, D. and Lin, C. J. and Eimer, W. A. and Quinti, L. and Gavrilles, E. P. and Garcia, S. N. and Heitman, S. N. and McGinty, D. and Cetinbas, M. and others},
title = {{The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function}},
journal = {Neuron},
year = {2026},
doi = {10.1016/j.neuron.2025.09.032},
pmid = {41109213},
url = {https://doi.org/10.1016/j.neuron.2025.09.032}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- 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.
Why it matters
This study found that the TREM2 T96K mutation increases Alzheimer's disease risk and impairs microglial function, including reduced clustering around amyloid-beta plaques and impaired uptake of amyloid-beta, in a sex-dependent manner in mice and cell cultures. It identifies a genetic risk mechanism and does not test any treatment, cure or prevention.
Study details
- Evidence strengthEarly
Limitations
The authors note it is unknown how a gain-of-function mutation produces phenotypes similar to loss-of-function mutations, and that whether T96K is protective against tauopathy-induced pathology, as reported for Trem2 knockout and R47H, remains to be tested.
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 43 of the 98 points we could judge it on, which is 44 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 2 / 5 | Rated “early” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 13 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 3 / 6 | Cited 4.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 13 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Ana Griciuc: h-index 14 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41109213) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 43 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 43 of the 98 points we could judge it on is 44 out of 100. |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.neuron.2025.09.032
- PubMed: 41109213
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 51.
Related studies in Laboratory science
Also tagged “macrophages”
363 studies in the library carry the topic tag “macrophages”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 363 tagged studies.