Models of the extracellular domain of TREM2 show that Nasu-Hakola disease–associated mutations are grossly inactivating by truncation, frameshift, or unfolding, that Alzheimer's disease (AD)–associated variants localize to a putative ligand-interacting region (PLIR) on the extracellular surface, and that FTD-associated variants are found in the hydrophobic core. This evidence concerns the gene TREM2 and frontotemporal dementia.