Blood-Based α-Synuclein Biomarkers in Parkinson's Disease: Molecular Diversity, Analytical Advances and Clinical Translation.

Early and accurate diagnosis of Parkinson's disease (PD) remains challenging in routine practice, as cardinal motor symptoms emerge only after substantial neurodegeneration has occurred. Blood-based biomarkers are therefore of considerable interest for identifying prodromal disease, enabling biologically stratified clinical trials, and supporting longitudinal monitoring. Among candidate markers, α-synuclein (α-Syn) is centrally relevant due to its fundamental role in PD pathogenesis. However, its peripheral measurement is complicated by marked molecular heterogeneity, uneven compartmental distribution, and analytical variability. In this narrative review, we examine the current evidence on blood-based α-Syn biomarkers with a focus on molecular diversity, compartmental biology, analytical platforms, and mechanisms governing central-peripheral exchange. We critically compare plasma, erythrocytes, and extracellular vesicle-based measurements and discuss the diagnostic implications of total, oligomeric, phosphorylated, and seeding-competent species. Recent advances in immunoassays, ultrasensitive technologies, mass spectrometry, and seed amplification assays (SAA) are also reviewed. Current evidence suggests that blood-based α-Syn assays hold promise, but their interpretation remains constrained by hemolysis, compartment-specific biology, assay heterogeneity, and limited longitudinal validation. Critically, no single blood-based α-Syn assay currently meets the performance standards required for standalone clinical application. Future progress will depend on methodological harmonization, multi-center and multi-ethnic studies, and integration with complementary biomarkers. A mechanistically grounded understanding of peripheral α-Syn dynamics is essential for developing clinically useful biomarker strategies for PD.