TREM2 is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. A rare R47H mutation in TREM2 is associated with increased Alzheimer's disease (AD) risk. In the 5XFAD mouse model of AD, TREM2 deficiency and haploinsufficiency lead to increased β-amyloid (Aβ) accumulation due to dysfunctional microglial responses, causing microglia to become apoptotic and fail to cluster around Aβ plaques. TREM2 senses anionic and zwitterionic lipids associated with fibrillar Aβ and exposed on damaged neurons. The R47H mutation impairs TREM2 detection of lipid ligands, suggesting that TREM2 detects damage-associated lipid patterns, sustaining microglia response to Aβ accumulation. TREM2 also supports microglia survival by synergizing with CSF-1R signaling. TREM2 binds to a broad array of anionic lipids, which are found in association with fibrillar Aβ and are also exposed during neuronal and glial cell death. The R47H mutation impairs TREM2 binding to anionic lipids. TREM2 is a receptor that detects damage-associated lipids, enabling microglia to sense Aβ accumulation and cell damage, as well as supporting microglia survival and Aβ reactive microgliosis. The study shows that TREM2 modulates Aβ accumulation in the 5XFAD mouse model of AD, reducing neuronal damage. TREM2 is essential for Aβ-reactive microgliosis, which involves microglial expansion and activation leading to clustering around Aβ plaques and subsequent Aβ removal. In the absence of TREM2, microglia are unable to survive, as evidenced by the accumulation of apoptotic microglia around Aβ plaques. TREM2 is a sensor for anionic and zwitterionic lipids that accumulate in the CNS during Aβ deposition. The R47H mutation impairs TREM2 recognition of lipid ligands. The study highlights the role of TREM2 in microglial response to Aβ and its importance in maintaining microglia survival and Aβ clearance.TREM2 is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. A rare R47H mutation in TREM2 is associated with increased Alzheimer's disease (AD) risk. In the 5XFAD mouse model of AD, TREM2 deficiency and haploinsufficiency lead to increased β-amyloid (Aβ) accumulation due to dysfunctional microglial responses, causing microglia to become apoptotic and fail to cluster around Aβ plaques. TREM2 senses anionic and zwitterionic lipids associated with fibrillar Aβ and exposed on damaged neurons. The R47H mutation impairs TREM2 detection of lipid ligands, suggesting that TREM2 detects damage-associated lipid patterns, sustaining microglia response to Aβ accumulation. TREM2 also supports microglia survival by synergizing with CSF-1R signaling. TREM2 binds to a broad array of anionic lipids, which are found in association with fibrillar Aβ and are also exposed during neuronal and glial cell death. The R47H mutation impairs TREM2 binding to anionic lipids. TREM2 is a receptor that detects damage-associated lipids, enabling microglia to sense Aβ accumulation and cell damage, as well as supporting microglia survival and Aβ reactive microgliosis. The study shows that TREM2 modulates Aβ accumulation in the 5XFAD mouse model of AD, reducing neuronal damage. TREM2 is essential for Aβ-reactive microgliosis, which involves microglial expansion and activation leading to clustering around Aβ plaques and subsequent Aβ removal. In the absence of TREM2, microglia are unable to survive, as evidenced by the accumulation of apoptotic microglia around Aβ plaques. TREM2 is a sensor for anionic and zwitterionic lipids that accumulate in the CNS during Aβ deposition. The R47H mutation impairs TREM2 recognition of lipid ligands. The study highlights the role of TREM2 in microglial response to Aβ and its importance in maintaining microglia survival and Aβ clearance.