Frontotemporal dementia
Summary
Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of neurodegenerative diseases affecting the frontal and temporal lobes, resulting in behavioral, personality, and language changes. Genetic forms are caused by mutations in GRN, MAPT, and C9orf72, among others. Microglial dysfunction is a prominent feature of multiple FTD subtypes.
Microglial Relevance
GRN mutations are among the most common causes of familial FTD. Progranulin is highly expressed in microglia and its deficiency causes lysosomal dysfunction, hyperactivated microglia, excessive synaptic pruning, and lipofuscinosis. GPNMB, a downstream marker of GRN deficiency, is elevated in GRN-FTD brains. C9orf72-FTD is associated with microglial activation and altered lysosomal function. Single-cell RNA-seq of FTD brain reveals microglial states distinct from those in AD. TREM2 heterozygous mutations cause Nasu-Hakola disease, which presents with an FTD-like syndrome.
Sources
- Progranulin mutations cause frontotemporal lobar degeneration (2006)
Last reviewed: June 1, 2026