Since 2015 single-cell sequencing has revealed that mutations in single human neurons track developmental and transcriptional history. Formation of all CNS cells is completed in the first year of life; early, common somatic neuronal mutations thus mainly reflect duplication mutations after conception. After terminal differentiation neuronal genes with high transcription rates are prone to somatic mutation compatible with transcriptional mutations.
At AAN 2024 12 of 16 at-risk germline loci in the APP gene (Alzheimer’s disease, AD) and 4 of 5 loci in the SNCA gene (Parkinson’s disease, PD) were shown to consist of somatic hypermutation (SHM) hotspots. Assuming similar transcriptional activity of both genes, at least one mutation of any SHM hotspot on both alleles for sporadic disease expression, and disregarding the importance of other genes, then a constant rate of ssDNA damage and mutation during transcription of the large number at-risk AD SHM hotspots suggest that sporadic AD is much more common (<122/42=<9-fold) than PD.