Significance Alzheimer’s disease (AD) is the most common dementia; no therapy halts its progression. AD pathology, including amyloid-β (Aβ) plaques, neurofibrillary tangles, and synapse loss, triggers microglial responses that modulate disease course. The TREM2 receptor promotes microglia responses to pathology and a variant, TREM2 ^R47H , impairs ligand binding and increases AD risk. Employing scRNA-seq, we asked: can an anti-TREM2 antibody, acting as a surrogate ligand, stimulate microglia in mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 ^CV ) or TREM2 ^R47H ? One systemic injection of anti-TREM2 restored microglia activation in TREM2 ^R47H mice but promoted limited activation in mice carrying TREM2 ^CV , which binds endogenous ligands. Thus, anti-TREM2 can strengthen microglial responses during AD, contingent on preexisting TREM2 engagement and basal activation.