Single-cell whole-genome sequencing reveals a shared pattern of excessive somatic mutations across C9ORF72 ALS, C9ORF72 FTD, and Alzheimer’s disease, dominated by 2-bp deletions. These mutations arise from aberrant topoisomerase 1 (TOP1)-mediated mutagenesis linked to oxidative DNA damage, identifying a unifying mechanism of neuronal genomic instability in neurodegeneration.