In summary, using VMAP as a discovery cohort, we find evidence that genetic regulation at the MS4A locus may confer protection against AD at least in part via augmentation of the TREM2 pathway, possibly increases in sTREM2 CSF reservoir in response to soluble Aβ pathology, replicating results in an independent dataset (N = 399) in ADNI. Here, TREM2 is linked to Alzheimer disease.