Single-neuron sequencing reveals widespread low-frequency somatic mutations in dementia brains

In a preprint analyzing postmortem human brain tissue, researchers sequenced 39,800 neurons from 52 individuals with sporadic frontotemporal lobar degeneration with TDP-43 pathology and 26 non-demented controls. The team used targeted single-nucleus amplicon sequencing on the superior temporal gyrus to profile TARDBP and other disease-associated genes. They identified widespread somatic mutations at frequencies below 1% across all studied genes. Notably, known ALS- and FTD-associated TARDBP variants appeared only in patient neurons. TARDBP carried the highest proportion of mutated neurons among the tested genes, yet this somatic burden was lower in donors who died at older ages. Furthermore, the C-terminal domain of TDP-43 showed fewer somatic mutations than its other domains, suggesting that cells carrying severe mutations may die before autopsy.