Toward brain-derived extracellular vesicles as biochemical biopsies of synucleinopathies

Abstract Synucleinopathies are defined by pathological α-synuclein states, including conformation, aggregation, modification, and seeding competence, that abundance alone cannot capture. Extracellular vesicles may preserve these states during transit from brain to blood, but mechanistic plausibility, diagnostic discrimination, and brain provenance are distinct claims. We argue that proteomics can interrogate vesicle identity, cargo and proteoforms, while unresolved provenance, pre-analytical variability, and incomplete clinical validation leave the biochemical biopsy concept plausible but unvalidated.