Mechanisms contributing to differential genetic risks for TREM2 R47H and R62H variants in Alzheimer's Disease

Coding variants in the microglial TREM2 ectodomain differentially (R47H> R62H) increase the risk of Alzheimers disease (AD). To define mechanisms responsible, we characterised neuropathology and transcriptomic responses in heterozygotes for these TREM2 variant alleles (TREM2var) and for common allele homozygotes (CV) in non-diseased and AD brain cortical tissue from 58 donors. Increased neurodegeneration in the TREM2var AD cortex was associated with genotype-dependent reductions in expression of Disease Associated Microglia (DAM) genes and increased expression of complement and Type I and II interferon pathways in microglia, phagocytosis and amyloid binding pathways and Disease Associated Astrocyte (DAA) genes in astrocytes, and growth factor, ubiquitination and apoptotic pathways in neurons. The microglial phenotypes and secondary differences in tissue {beta}-amyloid deposition and in astrocyte and neuronal responses describe a variably partial loss of TREM2 function with variant alleles (R47H>R62H) relative to CV and suggest mechanisms that could account for differences in genetic risks conferred.