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TREM2 risk variants and associated endophenotypes in alzheimer's disease
Janna I R Dijkstra, Lisa Vermunt, Vikram Venkatraghavan, Georgii Ozhegov, Emma M Coomans, Rik Ossenkoppele, Elsmarieke van de Giessen, Marc Hulsman et al.. Alzheimer's research & therapy, 2025-03-06
Topic: Genetics and APOE
TREM2 variant carriers (64 ± 7 years, 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying a TREM2 variant (64 ± 7 years, 52% female). We observed no differences in MMSE, neuropsychological domains (except less impaired visuospatial functioning in TREM2 carriers), MRI scores, CSF biomarkers, EEG, structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N). Carriers did show faster cognitive decline (MMSE points per year 0.6 ± 0.3, P fdr = 0.099) compared to non-carriers. Notably, both R47H and T96K carriers exhibited faster cognitive decline (P < 0.05), and R47H carriers even showed an increased rate of death after diagnosis (P = 0.034). In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline. This study shows that while carriers of TREM2 risk variants cannot be distinguished based on clinical presentation at baseline compared to non-carriers, they do exhibit a faster global cognitive decline. Variant-specific analyses indicate that especially R47H and T96K carriers drive this association. These results highlight the importance of considering variant-specific effects for understanding the role of TREM2 biology in AD. The rich phenotype information can inform clinical stage drug development.
Key findings
- TREM2 variant carriers (64 ± 7 years, 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying a TREM2 variant (64 ± 7 years, 52% female).
- We observed no differences in MMSE, neuropsychological domains (except less impaired visuospatial functioning in TREM2 carriers), MRI scores, CSF biomarkers, EEG, structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N).
- Carriers did show faster cognitive decline (MMSE points per year 0.6 ± 0.3, P fdr = 0.099) compared to non-carriers.
- Notably, both R47H and T96K carriers exhibited faster cognitive decline (P < 0.05), and R47H carriers even showed an increased rate of death after diagnosis (P = 0.034).
- In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline.
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Study details
- Participants123
- Effect size7.8%
- Evidence strengthModerate
How this study scored 59/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 33 of the 56 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer's research & therapy) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 123 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40051009) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 33 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 33 of the 56 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Dijkstra, J. I. R., Vermunt, L., Venkatraghavan, V., Ozhegov, G., Coomans, E. M., Ossenkoppele, R., et al. (2025). TREM2 risk variants and associated endophenotypes in alzheimer's disease. Alzheimer's research & therapy. https://doi.org/10.1186/s13195-025-01700-2
Vancouver
Dijkstra JIR, Vermunt L, Venkatraghavan V, Ozhegov G, Coomans EM, Ossenkoppele R, et al. TREM2 risk variants and associated endophenotypes in alzheimer's disease. Alzheimer's research & therapy. 2025. doi:10.1186/s13195-025-01700-2. PMID: 40051009.
BibTeX
@article{dijkstra2025-40051009,
author = {Dijkstra, Janna I R and Vermunt, Lisa and Venkatraghavan, Vikram and Ozhegov, Georgii and Coomans, Emma M and Ossenkoppele, Rik and van de Giessen, Elsmarieke and Hulsman, Marc and others},
title = {{TREM2 risk variants and associated endophenotypes in alzheimer's disease}},
journal = {Alzheimer's research \& therapy},
year = {2025},
doi = {10.1186/s13195-025-01700-2},
pmid = {40051009},
url = {https://doi.org/10.1186/s13195-025-01700-2}
}
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