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Conventional clinical diagnosis is often delayed until after substantial neuronal degeneration has occurred. Recent advances in \u03b1\u2010syn seed amplification assays (\u03b1\u2010syn SAAs), including real\u2010time quaking\u2010induced conversion (RT\u2010QuIC) and protein misfolding cyclic amplification (PMCA), have revolutionized PD biomarker research. These assays exploit the prion\u2010like seeding and propagation properties of pathological \u03b1\u2010syn to amplify trace aggregates in biological samples with exceptional sensitivity and specificity. Here, we summarize the mechanistic principles and biophysical underpinnings of \u03b1\u2010syn SAAs, compare their diagnostic performance across biospecimens such as cerebrospinal fluid, skin, blood, and saliva, and evaluate their potential for differential diagnosis among synucleinopathies. We further discuss the integration of SAAs with other biomarkers including \u03b1\u2010syn oligomer ELISAs, neurofilament light chain assays, and dopaminergic PET\/SPECT imaging. Emerging developments, such as same\u2010day RT\u2010QuIC, quantitative kinetic readouts, and peripheral blood\u2010based assays, are accelerating clinical translation. Despite challenges in assay standardization, strain discrimination, and regulatory validation, \u03b1\u2010syn SAAs hold transformative potential for early diagnosis, patient stratification, and monitoring of therapeutic efficacy in PD. Their convergence with artificial intelligence, organoid modeling, and multimodal biomarker frameworks promises to redefine precision medicine in PD and other synucleinopathies.<\/jats:p>","DOI":"10.1002\/med.70080","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T10:53:42Z","timestamp":1784199222000},"page":"1922-1938","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b1\u2010Synuclein Seeds Amplification Assays for Parkinson's Disease and Related Synucleinopathies"],"prefix":"10.1002","volume":"46","author":[{"given":"Rosalie","family":"Elvira","sequence":"first","affiliation":[{"name":"Department of Neurology National Neuroscience Institute Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-6540","authenticated-orcid":false,"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Neurology Zhujiang Hospital of Southern Medical University Guang Zhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4581-6524","authenticated-orcid":false,"given":"Yun\u2010Cheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng King","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Neurology National Neuroscience Institute Singapore Singapore"},{"name":"Department of Neurology Singapore General Hospital Singapore Singapore"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders Duke\u2010NUS Medical School Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-4163","authenticated-orcid":false,"given":"Zhi Dong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology National Neuroscience Institute Singapore Singapore"},{"name":"Signature Research Program in Neuroscience and Behavioral Disorders Duke\u2010NUS Medical School Singapore 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