TREM2 risk variants and associated endophenotypes in alzheimer’s disease

Mar 6, 2025Alzheimer's research & therapy

TREM2 gene variants and related traits in Alzheimer's disease

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Abstract

variant carriers (n = 123) show a faster cognitive decline compared to non-carriers (n = 1,459) despite similar clinical presentations at baseline.

Both groups had similar age and gender distributions, with carriers averaging 64 years and 54% female.
No significant differences were observed in cognitive assessments, neuropsychological domains, or various imaging and biomarker measures, except for less impaired visuospatial functioning in carriers.
TREM2 variant carriers experienced a cognitive decline rate of 0.6 points per year on the scale, approaching statistical significance.
R47H and T96K carriers exhibited notably faster cognitive decline compared to non-carriers, with R47H also associated with increased mortality post-diagnosis.
The findings suggest that while the clinical presentation is similar, the underlying genetic variants may influence the progression of Alzheimer's disease differently.

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BACKGROUND: Rare variants of the triggering receptor expressed on myeloid cell 2 () 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 , 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 = 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. fdr

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.

Key numbers

−1.4

Cognitive Decline Increase

Points decline per year of follow-up for R47H carriers

1.60

Mortality Risk Increase

Hazard Ratio for mortality risk in R47H carriers

123 of 1582

Cohort Size

Variant carriers out of total AD patients in the cohort

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TREM2 risk variants and associated endophenotypes in alzheimer’s disease

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