The findings of microglial-related pathway and DAM gene expression differences between the 5XFAD × TREM2−/− and 5XFAD × TREM2+/− mice, combined with differing microglial plaque-association but similar NP tau pathology after AD-tau injection, emphasize that TREM2 heterozygous and KO mice are distinct and that the former may better model the heterozygous TREM2 variants linked to AD risk. Here, MAPT is linked to Alzheimer disease.