Very recently, Jain et al. reported an interesting finding that chronic activation of TREM2 receptor with a TREM2 antibody increased the activation of peri-plaque microglia, and surprisingly aggravated tau pathology and neurodegeneration in a mouse model of amyloidosis in which tau was injected directly into the brain to induce Aβ-dependent tau seeding/spreading.234 It is possible that the adverse effect of TREM2 at the later stage of AD is caused by the chronic activation of it (Fig. 5). This evidence concerns the gene MAPT and Alzheimer disease.