The TREM2 H157Y variant is associated with more severe neurodegeneration in Alzheimer's disease and altered immune-related processes

INTRODUCTION

Multiple TREM2 variants are associated with an increased risk of Alzheimer's disease (AD). TREM2 H157Y is the only variant located at the proteolytic cleavage site that enhances TREM2 protein shedding. While this variant is associated with increased AD risk predominantly in the Chinese population, its impact on AD pathology is largely unknown.

METHODS

We conducted an in-depth study integrating clinical cases, neuroimaging data, and blood proteomic data.

RESULTS

TREM2 H157Y variant carriers with AD exhibit more severe AD pathology, more severe neurodegeneration, and more rapid clinical progression. Cognitively normal individuals carrying the variant show changes in blood proteins that are associated with neurodegeneration and inflammation. Moreover, the TREM2 H157Y variant is associated with altered immune and vascular processes irrespective of disease state.

DISCUSSION

These findings highlight the clinical implications of the TREM2 H157Y variant and the use of blood proteomic data to investigate the effects of genetic variants on disease-related endophenotypes.

Highlights

• The TREM2 H157Y variant is associated with more rapid clinical progression of Alzheimer's disease only in the presence of the apolipoprotein E (APOE) ε4 allele.
• The TREM2 H157Y variant is associated with neurodegeneration, irrespective of disease state.
• The TREM2 H157Y variant is associated with altered immune and vascular processes, irrespective of disease state.
• Cognitively normal TREM2 H157Y carriers show altered disease-associated blood proteins related to peripheral immune response.
• Blood proteomic data can be used to study the impacts of disease-associated genetic variants on disease outcomes and biological processes involved in pathogenesis.