Heterozygous TREM2 mutations in frontotemporal dementia.

A causative association was recently demonstrated between homozygous TREM2 mutations and frontotemporal dementia (FTD)-like syndrome and between heterozygous TREM2 exon2 genetic variations and late-onset Alzheimer's disease (AD). The objective of this study was to evaluate whether heterozygous TREM2 genetic variations might be associated to the risk of FTD. TREM2 exon 2 was sequenced in a group of 1030 subjects-namely, 352 patients fulfilling clinical criteria for FTD, 484 healthy control subjects (HCs), and 194 patients with AD. The mutation frequency and the associated clinical characteristics were analyzed. We identified 8 missense and nonsense mutations in TREM2 exon 2 in 24 subjects. These mutations were more frequent in patients with FTD than in HCs (4.0% vs. 1.0%, p = 0.005). In particular, TREM2 Q33X, R47H, T66M, and S116C mutations were found in FTD and were absent in HCs. These mutations were associated with either the semantic variant of primary progressive aphasia or the behavioral variant FTD phenotypes. The FTD and AD groups were not significantly different with regard to TREM2 genetic variation frequency (AD: 2.6%, p = 0.39). Heterozygous TREM2 mutations modulate the risk of FTD in addition to increasing susceptibility to AD. Additional studies are warranted to investigate the possible role of these mutations in the pathogenesis of neurodegenerative disorders.