The study investigates the role of triggering receptor expressed on myeloid cells 2 (TREM2) in Alzheimer's disease (AD) using the 5XFAD mouse model. TREM2 deficiency or haploinsufficiency increases β-amyloid (Aβ) accumulation due to dysfunctional microglial response, leading to apoptosis and reduced clustering around Aβ plaques. TREM2 senses a broad array of anionic and zwitterionic lipids associated with Aβ and neuronal damage. The R47H mutation, which is associated with AD, impairs TREM2's detection of these lipid ligands. TREM2 is essential for microglial survival and reactive microgliosis, and its deficiency affects microglial clustering around Aβ plaques. TREM2 acts as a sensor for damage-induced lipids, supporting microglial response to Aβ accumulation and neuronal damage.The study investigates the role of triggering receptor expressed on myeloid cells 2 (TREM2) in Alzheimer's disease (AD) using the 5XFAD mouse model. TREM2 deficiency or haploinsufficiency increases β-amyloid (Aβ) accumulation due to dysfunctional microglial response, leading to apoptosis and reduced clustering around Aβ plaques. TREM2 senses a broad array of anionic and zwitterionic lipids associated with Aβ and neuronal damage. The R47H mutation, which is associated with AD, impairs TREM2's detection of these lipid ligands. TREM2 is essential for microglial survival and reactive microgliosis, and its deficiency affects microglial clustering around Aβ plaques. TREM2 acts as a sensor for damage-induced lipids, supporting microglial response to Aβ accumulation and neuronal damage.