Heterozygous TREM2 mutations in frontotemporal dementia

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Genomics

Background:

• Homozygous TREM2 mutations link to frontotemporal dementia (FTD)-like syndromes.
• Heterozygous TREM2 variations are associated with late-onset Alzheimer's disease (AD).

Purpose of the Study:

• To investigate the association between heterozygous TREM2 genetic variations and the risk of developing FTD.
• To analyze mutation frequency and clinical characteristics in FTD patients with TREM2 variations.

Main Methods:

• Sequencing of TREM2 exon 2 in 1030 subjects (352 FTD patients, 484 healthy controls, 194 AD patients).
• Analysis of mutation frequency and correlation with clinical phenotypes.
• Comparison of mutation frequencies between FTD, AD, and healthy control groups.

Main Results:

• Eight missense and nonsense mutations in TREM2 exon 2 were identified in 24 subjects.
• Mutations were significantly more frequent in FTD patients (4.0%) compared to healthy controls (1.0%, p=0.005).
• Specific mutations (Q33X, R47H, T66M, S116C) were found in FTD patients but not in controls, associated with semantic or behavioral variant FTD phenotypes.

Conclusions:

• Heterozygous TREM2 mutations modulate the risk for FTD.
• These mutations contribute to FTD susceptibility, similar to their known role in AD.
• Further research is needed to elucidate the role of TREM2 mutations in neurodegenerative disease pathogenesis.