Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia

Frontotemporal dementia (FTD) caused by progranulin (GRN) mutations is associated with pronounced thalamic degeneration, yet the cellular basis of selective thalamic vulnerability remains poorly understood. Here, we generated an integrated single-nucleus RNA-sequencing atlas of the human antero-median thalamus comprising 331,065 nuclei from 92 individuals across three independent cohorts spanning GRN-associated FTD, sporadic FTD with TDP-43 proteinopathy, Alzheimer's disease (AD), and neurologically normal aging. While AD samples exhibited minimal thalamic cellular remodeling, FTD cases were characterized by highly selective and reproducible degeneration of discrete neuronal populations across independent cohorts. In particular, two inhibitory neuronal populations were markedly depleted in FTD, which was accompanied by impaired GABAergic communication. Among excitatory neurons, RNF220+ neurons exhibited extensive transcriptional dysregulation, altered sterol metabolic pathways, together with robust TDP-43-associated STMN2 cryptic splicing pathology and reduced glutamatergic signaling. By contrast, RNF220- excitatory neurons were comparatively resilient, displaying preserved neuronal communication, and resistance to STMN2 cryptic exon accumulation. In control individuals, RNF220- excitatory neurons exhibited elevated GRN expression and an intrinsic enrichment of cytoskeletal maintenance programs. Spatial transcriptomics confirmed the anatomical distribution of vulnerable neuronal populations in the adult human thalamus. In parallel, FTD samples demonstrated expansion of vascular-associated and lymphocyte populations as well as reactive glial signatures. Together, these findings define a cellular framework for selective vulnerability and resilience in the human FTD thalamus and identify intrinsic molecular programs associated with resistance to neurodegeneration.