Parkinson’s Disease: From Gene–Environment Risk to Precision Therapy

Parkinson’s disease (PD) is a progressive and heterogeneous neurodegenerative disorder and one of the fastest-growing causes of neurological disability worldwide. Although classically defined by motor manifestations arising from nigrostriatal dopaminergic degeneration, PD is now recognized as a multisystem disorder in which non-motor symptoms—including autonomic dysfunction, neuropsychiatric features, cognitive impairment, and sleep-related disorders—often precede motor onset by years or decades, defining a clinically meaningful prodromal phase. The aetiology of PD reflects a complex interplay between genetic susceptibility and environmental exposure. Approximately 20% of cases are associated with identifiable pathogenic variants, most commonly involving LRRK2, GBA1, and SNCA, while the majority arise from gene–environment interactions involving toxicant exposure, lifestyle factors, and common genetic risk variants. Despite major advances in understanding disease biology, current therapies remain fundamentally symptomatic. Dopaminergic pharmacotherapy and device-aided interventions improve motor function but do not alter disease progression, and non-motor symptoms remain a dominant determinant of disability and reduced quality of life. Recent conceptual advances propose redefining PD as a biologically defined α-synucleinopathy. Emerging biomarkers, including α-synuclein seed amplification assays in cerebrospinal fluid and peripheral tissues, offer unprecedented opportunities for early diagnosis, biological stratification, and precision clinical trials. However, translation into disease modification has been limited by late-stage intervention, reliance on clinically defined populations, restricted trial generalisability, and profound global inequities in access to advanced diagnostics and therapies. This review synthesizes current evidence on PD epidemiology, diagnosis, aetiology, progression, and treatment, with particular emphasis on gene–environment interactions, the functional limitations of existing therapeutic paradigms, and the transformative—but as yet unrealized—potential of biological classification. By identifying key mechanistic, clinical, and implementation gaps, the review frames future directions that prioritize prevention, early biological definition, patient-centred functional outcomes, and equitable precision care across diverse healthcare settings.