In amyloidosis mouse models, microglial activation follows a two-step process: an initial TREM2-independent phase characterized by the downregulation of homeostatic checkpoint genes and the upregulation of neurodegeneration-associated markers, followed by a TREM2-dependent phase essential for the induction of lipid metabolism and phagocytosis-related genes involved in Aβ clearance. Here, TREM2 is linked to amyloidosis.