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 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.

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.

INTRODUCTION: Cognitive resilience refers to maintaining cognitive function despite Alzheimer's disease (AD) pathophysiology. METHODS: We analyzed amyloid-positive individuals across clinical stages of AD in two cohorts: the Amsterdam Dementia Cohort (ADC, N = 1036) and Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 685). Cognitive resilience was conceptualized from a canonical correlation analysis of magnetic resonance imaging and neuropsychological data in each cohort separately. Model validation involved education as a resilience proxy and key genetic factors (apolipoprotein E [APOE] ε4 and APOE ε2) of AD. We explored associations between 83 AD risk loci and cognitive resilience. RESULTS: Resilience was correlated with education (ADC: β = 0.144, p < 0.001; ADNI: β = 0.149, p < 0.001) and APOE ε4 (β_{meta-analysis}= –0.052, p = 0.014). Exploratory single nucleotide polymorphism meta-analysis identified potential involvement of genetic variants around genes UNC5CL, USP6NL, and TPCN1 in lower, and genes COX7C and MINDY2 in higher resilience. DISCUSSION: Our novel resilience approach showed conceptual validity and potential for future discovery of resilience-related genetic variants. Highlights: ·We define a novel approach to resilience using canonical correlation analysis (CCA). ·Apolipoprotein E ε4 is linked to lower resilience, suggesting increased vulnerability. ·Genetic loci around COX7C and MINDY2 are potentially involved in higher resilience. ·This novel approach may be used for multi-cohort studies such as genome-wide association studies in the future.