Abstract
Misfolded alpha-Synuclein (α-Syn) accumulation is the defining molecular pathology of Parkinson’s disease (PD), yet blood-based assays remain challenged by the high background of peripheral α-Syn originating mainly from red blood cells. Neuronal extracellular vesicles (EVs) circulating in blood offer a biologically enriched source of brain-derived α-Syn proteoforms, but their ultralow abundance has hindered reliable detection. Here, we introduce an organic electrochemical transistor–based multiparametric diagnostic assay that simultaneously detects total, aggregated, and serine-129–phosphorylated α-Syn proteoforms in serum L1CAM
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EVs. The platform achieves low femtomolar sensitivity in buffer and robust analytical performance in clinical specimens. In a cohort of 66 individuals, including prodromal and clinically diagnosed patients with PD, combining the three proteoform readouts distinguished PD from controls with 90.9% accuracy (88.6% sensitivity and 90.9% specificity). By electronically amplifying and resolving multiple neuronal α-Syn signatures in blood, this assay enables a minimally invasive diagnostic tool for early-stage PD and provides a path toward therapeutic intervention during the window when disease-modifying treatments are likely to be most effective.