Variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2) were recently identified as one of the most important genetic risk factors for Alzheimer’s disease (AD). In particular, the most common TREM2 variant, R47H, increases AD risk approximately 3-fold.  TREM2 is exquisitely expressed in microglia, the resident innate-immune cells of the brain. Most of what is known suggests that the TREM2 R47H mutation may mimic some aspects of loss-of-function of TREM2. Microglia that lack TREM2 appear to be less responsive to combating AD-linked changes in the brain such as amyloid pathology. However, loss of TREM2 also appears to be associated with worsening of inflammation in the brain, possibly through enhancing pro-inflammatory responses and dampening healing responses.

TREM2-R47H is a strong genetic risk factor for AD, but there are major gaps in our current understanding of the mechanisms underlying this association. This proposal harnesses the combined expertise of experts in AD clinical care and pathophysiology, microglial contributions to neurodegeneration, and precision medicine to tackle several critical questions about how TREM2 R47H drives increased AD risk, including (1) deeply phenotyping TREM2-R47H carriers in a comprehensive cognitive, clinical, imaging, and biomarker program; (2) developing assays and biomarkers of TREM2-R47H effects on microglial function in patient-derived cultures and biofluids; and (3) conducting computational analysis of TREM2-R47H structure and a virtual screens for therapies