Parkinson's disease in transition: Genetics, biomarkers, and emerging therapeutics.

Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide, largely driven by the aging global population, and poses major challenges in clinical management due to progressive disability, the emergence of symptoms insufficiently controlled by current therapies, and treatment-related complications. In this Review, we revisit the definition of PD beyond its clinical manifestations, emphasizing the evolving framework of biological classification. We examine advances in genetics and explore the structural and physiological roles of α-synuclein, with particular attention to post-translational modifications, their contributions to neurodegeneration, and the existence of disease-specific α-synuclein strains that underlie pathological propagation. We highlight recent progress in diagnostic technologies, including seed amplification assays and PET tracers for pathological α-synuclein detection, as well as updates in MRI-based imaging and digital biomarkers to support early detection and differentiation of PD from atypical parkinsonian syndromes. Finally, we review the current therapeutic landscape, encompassing pharmacological therapies, surgical approaches such as deep brain stimulation, and emerging neuromodulation strategies, including adaptive deep brain stimulation, transcranial magnetic stimulation, and focused ultrasound. Together, these strategies will bridge the gap to transform both the understanding and clinical care of PD in the coming decade.