TREM2 risk variants and associated endophenotypes in alzheimer’s disease
(2025) In Alzheimer's Research and Therapy 17(1).- Abstract
Background: Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are strong risk factors for Alzheimer’s disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown what the effect of TREM2 variants is on the AD phenotype. Methods: Here we studied a full range of clinical and biomarker measures in a large cohort of TREM2 variant carriers (n = 123, 7.8%, i.e., R62H n = 66, R47H n = 26, T96K n = 16, other TREM2 variants n = 17) compared to confirmed non-carriers (n = 1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort. Secondly, we explored whether specific TREM2 variants were associated with distinct clinical measures compared to the reference... (More)
Background: Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are strong risk factors for Alzheimer’s disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown what the effect of TREM2 variants is on the AD phenotype. Methods: Here we studied a full range of clinical and biomarker measures in a large cohort of TREM2 variant carriers (n = 123, 7.8%, i.e., R62H n = 66, R47H n = 26, T96K n = 16, other TREM2 variants n = 17) compared to confirmed non-carriers (n = 1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort. Secondly, we explored whether specific TREM2 variants were associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort. Results: 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, Pfdr = 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. Conclusions: 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.
(Less)
- author
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer’s disease, Clinical measures, TREM2
- in
- Alzheimer's Research and Therapy
- volume
- 17
- issue
- 1
- article number
- 57
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:40051009
- scopus:86000102158
- ISSN
- 1758-9193
- DOI
- 10.1186/s13195-025-01700-2
- language
- English
- LU publication?
- yes
- id
- 954c43a6-2452-4103-9dc2-2c0a70d2ed04
- date added to LUP
- 2025-06-09 09:41:26
- date last changed
- 2025-07-07 12:35:23
@article{954c43a6-2452-4103-9dc2-2c0a70d2ed04,
abstract = {{<p>Background: Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are strong risk factors for Alzheimer’s disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown what the effect of TREM2 variants is on the AD phenotype. Methods: Here we studied a full range of clinical and biomarker measures in a large cohort of TREM2 variant carriers (n = 123, 7.8%, i.e., R62H n = 66, R47H n = 26, T96K n = 16, other TREM2 variants n = 17) compared to confirmed non-carriers (n = 1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort. Secondly, we explored whether specific TREM2 variants were associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort. Results: 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<sub>fdr</sub> = 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. Conclusions: 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.</p>}},
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 de Geus, Christa M. and van der Flier, Wiesje M. and Sikkes, Sietske A.M. and Barkhof, Frederik and Tijms, Betty and Gouw, Alida A. and de Haan, Willem and Vijverberg, Everard G.B. and Pijnenburg, Yolande A.L. and Holstege, Henne and Teunissen, Charlotte E. and van der Lee, Sven J.}},
issn = {{1758-9193}},
keywords = {{Alzheimer’s disease; Clinical measures; TREM2}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Alzheimer's Research and Therapy}},
title = {{TREM2 risk variants and associated endophenotypes in alzheimer’s disease}},
url = {{http://dx.doi.org/10.1186/s13195-025-01700-2}},
doi = {{10.1186/s13195-025-01700-2}},
volume = {{17}},
year = {{2025}},
}