TREM2 Risk Variants with Alzheimer Disease Differ in Rate of Cognitive Decline

Abstract

Rare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are major risk factors for Alzheimers disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown whether carriers of a TREM2 risk variant have a clinically distinct AD phenotype. Here we studied a full range of clinical 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. TREM2 variant carriers (mean age at diagnosis 64.4 years (SD {+/-}7.1), 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying a TREM2 variant (mean age at diagnosis 64.4 {+/-}7.0, 52% female). Specifically, we observed no differences in MMSE, most neuropsychological domains (except visuospatial functioning), MRI scores, CSF biomarkers, and EEG. Also, in an exploratory analysis of neuroimaging measures, including structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N), TREM2 variant carriers showed similar atrophy patterns and similar abnormal tracer binding compared to non-carriers. Despite not being different at baseline, carriers did show faster cognitive decline in follow-up. Carriers declined 0.63 {+/-}0.25 points on the MMSE more per year compared to non-carriers, but there was no difference in the hazard rate of death after diagnosis. Finally, we explored whether specific TREM2 variants are associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort. Notably, both R47H and T96K carriers exhibited faster cognitive decline, and R47H carriers even showed an increased rate of death after diagnosis. In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline. This study presents a detailed overview of the clinical measures in AD patients carrying a TREM2 risk variant, and it shows that carriers of TREM2 risk variants cannot be distinguished based on clinical presentation at baseline. However, carriers exhibit a faster global cognitive decline compared to non-carriers. Variant-specific analyses suggest that especially R47H and T96K carriers drive the association of TREM2 variants with faster cognitive decline.