A Biological Framework for Parkinson's Disease: Advances in α-Synuclein-Centered Biomarkers and Staging.

Parkinson's disease (PD) is a neurodegenerative disorder marked by substantial heterogeneity in pathological distribution, disease trajectories, and coexisting neuropathologies. Despite this biological complexity, current diagnosis and staging of PD remain largely anchored in clinical manifestations. Neuronal aggregation of misfolded α-synuclein and degeneration of the nigrostriatal dopaminergic system precede the onset of motor symptoms; this phase is termed the prodromal stage of PD. Therefore, clinically based frameworks inherently limit early detection and stratification. In contrast, Alzheimer's disease has undergone a paradigm shift toward a biomarker-driven biological definition, prompting a similar reappraisal of PD as a biologically defined disease continuum. Accumulating evidence indicates that pathological α-synuclein aggregates in PD extend beyond the central nervous system and exhibit heterogeneous patterns of initiation and propagation. Methodological advances have expanded the capacity to detect these pathological species in vivo. In particular, α-synuclein seed amplification assays (SAA) enable the detection of seeding-competent α-synuclein species in biofluids and peripheral tissues, providing evidence consistent with α-synuclein pathology; however, SAA should not be interpreted as a direct reflection of disease stage, progression, or pathological burden. Furthermore, the development of α-synuclein positron emission tomography ligands offers the prospect of non-invasive visualization of pathological burden, spatial distribution, and longitudinal target engagement, thereby complementing biofluid-based approaches. Together, these biomarker advances underpin emerging biologically anchored classification and staging frameworks, such as the SynNeurGe system and the Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS). These frameworks integrate α-synuclein pathology, neurodegeneration, genetic background, and clinical features to define disease identity and progression across asymptomatic, prodromal, and manifest stages. We synthesize recent advances in α-synuclein-centered biomarkers and biological staging frameworks and discuss how their convergence is beginning to reshape PD from a primarily symptom-based diagnosis toward a molecularly grounded disease continuum. This transition has the potential to complement clinically defined PD with biologically informed perspectives.