We read with great interest the article by Guerreiro et al1 on the loss of function of the triggering receptor expressed on myeloid cells 2 (TREM2) gene causing Nasu-Hakola disease (NHD) and some frontotemporal dementia (FTD)–like diseases.1,2 Recently, TREM2 allele variants were also found to be associated with Alzheimer disease (AD).3 However, NHD, FTD-like disease, and AD differ enormously regarding the mechanism of disease, clinical aspects, and neuropathological findings. How can these differences be conciliated?