Single-neuron sequencing reveals widespread low-frequency somatic mutations in dementia brains
Human neurons from frontotemporal lobar degeneration patients showed ultra-low-frequency TARDBP variants that were less abundant in individuals who died at older ages.
bioRxiv : the preprint server for biology · Bidhan V et al. · Paper published 22 Sep 2026
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.
Why it matters
Accumulating somatic mutations in long-lived, post-mitotic cells represent a key facet of brain aging and neurodegeneration. Demonstrating that ultra-low-frequency mosaic variants arise in specific disease genes clarifies how localized genetic errors could influence neuronal survival across the lifespan.
Caveats
The study is a preprint that has not yet undergone peer review. Findings are based on postmortem tissue from a single cortical region, meaning surviving neurons at autopsy may introduce survival bias.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Targeted single-nucleus sequencing of 39,800 neurons reveals extensive low-frequency somatic variants
Bidhan V, Wynants S, Swings T et al.
bioRxiv : the preprint server for biology · 22 Sep 2026 · Preprint, not yet peer-reviewed
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