The genes encoding the microglial receptors CD33 and TREM2 have been associated with Alzheimer disease (AD) in GWASs. Here, the authors investigated crosstalk between these two receptors. Knockout of Cd33 alone decreased amyloid-β (Aβ) pathology and improved cognition in the 5xFAD mouse model of AD, effects that were abrogated by additional Trem2 knockout. As Aβ pathology and neurodegeneration were exacerbated in Trem2-/- 5xFAD mice, the authors conclude that TREM2 acts downstream of CD33, and that inhibiting CD33 and/or increasing the activity of TREM2 could represent novel therapeutic approaches.