On the one hand, sTREM2 production by receptor shedding is thought to negatively regulate TREM2 function, as the AD associated H157Y TREM2 variant promotes this shedding, leading to reduced TREM2-dependent phagocytosis (Schlepckow et al., 2017; Thornton et al., 2017). Here, TREM2 is linked to Alzheimer disease.