The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's disease by impairing microglial function.

We previously reported that T96K is a gain-of-function mutation in TREM2 based on its ability to increase ligand-dependent activation. Here, we show that TREM2T96K increases risk for Alzheimer's disease (AD) in a whole-genome sequencing dataset comprised of family-based and case-control samples. Trem2T96K also reduced clustering of microglia around β-amyloid (Aβ) plaques exclusively in female 5xFAD mice. Furthermore, T96K decreased levels of soluble Trem2 in female 5xFAD mice and human microglial cell cultures. We also observed impaired uptake of Aβ in Trem2T96K knockin microglial cells. Moreover, Trem2T96K reduced total area of phagocytic microglia, specifically in female 5xFAD mice. Single-cell RNA sequencing (scRNA-seq) profiling of microglia revealed that Trem2T96K impairs the transition of homeostatic microglia into disease-associated microglia (DAM) in female 5xFAD mice. Downregulated inflammatory pathways associated with Trem2T96K included interleukin (IL)-6/JAK/STAT3, complement, and interferon (IFN)-γ response. Collectively, our results indicate that, like the loss-of-function mutation R47H, Trem2T96K adversely affects microglial function in a sex-dependent manner.