A possible explanation for the modest effect of TDP-43 vaccination in rNLS8 mice may be the high and widespread deposition of TDP-43 aggregates in this model, which clearly exceeds the pathology in human ALS/FTD and cannot recapitulate focal onset and spreading of TDP-43 pathology across different brain regions over time [9, 48]. This evidence concerns the gene TARDBP and frontotemporal dementia.