AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). Using transcriptomic analysis at the single-nuclei level from brain tissue of AD patients with the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2.