Our study in a large cohort of 704 patients, including 37 genetically and 31 pathologically confirmed samples as well as in an independent validation cohort of 287 patients with 34 genetically confirmed cases, shows that plasma EVs inform about tau and TDP-43 pathology in bvFTD, and can additionally discriminate patients with ALS and PSP from healthy and neurodegenerative disease controls with high diagnostic accuracy (AUC > 0.91). This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.