Parkinson's Disease: From Gene-Environment Risk to Precision Therapy

Abstract

Parkinson's disease (PD) is a progressive and heterogeneous neurodegenerative disorder and one of the fastest-growing causes of neurological disability worldwide. Although historically defined by motor manifestations resulting from nigrostriatal dopaminergic degeneration, PD is now recognized as a multisystem disorder. Non-motor features-including autonomic dysfunction, neuropsychiatric symptoms, cognitive impairment, and sleep-related disorders-frequently precede motor onset by years or even decades, delineating a clinically meaningful prodromal phase. The aetiology of PD reflects a complex interplay between genetic susceptibility and environmental exposures. Approximately 20% of cases are linked to identifiable pathogenic variants, most commonly in LRRK2, GBA1, and SNCA, whereas the majority arise from cumulative interactions among environmental factors, lifestyle determinants, and common genetic risk variants rather than from single causal mechanisms. Despite substantial advances in understanding disease biology, current therapies remain fundamentally symptomatic. Dopaminergic pharmacotherapy and device-aided interventions improve motor function and, in selected contexts, functional outcomes, but they do not modify disease progression. Non-motor symptoms remain a dominant driver of disability and reduced quality of life. Recent conceptual frameworks 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 to define biological disease, enable early detection, and stratify patients. However, biomarker positivity currently informs diagnosis and classification rather than prognostication or therapeutic selection, and validated intermediate endpoints linking biomarker change to sustained functional benefit remain lacking. Consequently, translation into disease-modifying therapies has been constrained by late-stage intervention, reliance on clinically defined populations, limited trial generalizability, and marked global inequities in access to advanced diagnostics and treatments. This narrative review synthesizes current evidence on PD epidemiology, diagnosis, aetiology, progression, and treatment, emphasizing gene-environment interactions, convergence on shared pathogenic pathways, limitations of existing therapeutic paradigms, and the as-yet unrealized potential of biologically informed precision care.

Keywords: Parkinson’s disease; biomarkers; disease modification; gene–environment interaction; health equity; precision medicine; α-synucleinopathy.

Figure 1

Temporal dissociation between neurodegeneration, clinical phenotypes, and diagnostic thresholds in Parkinson’s disease. This conceptual framework depicts PD as a prolonged, biologically progressive disorder in which neurodegeneration, symptom expression, and clinical diagnosis are temporally uncoupled. Time is shown relative to clinical diagnosis (year 0), spanning presymptomatic, non-motor–predominant, and motor-dominant phases. The vertical axis represents relative integrity of the nigrostriatal dopaminergic system rather than absolute neuronal counts. The dashed trajectory illustrates a schematic pattern of dopaminergic decline and does not imply fixed quantitative thresholds or uniform rates of progression. Non-motor features—including hyposmia, constipation, rapid eye movement (REM) sleep behaviour disorder, anxiety, depression, cognitive dysfunction, hallucinations, and disturbances of iron metabolism—emerge early, often decades before diagnosis, reflecting early involvement of extranigral, autonomic, limbic, and brainstem networks. These manifestations frequently contribute substantially to functional impairment and reduced quality of life but remain under-represented in motor-centred diagnostic frameworks. In contrast, cardinal motor features—bradykinesia, tremor, rigidity, and postural instability—typically arise later, coinciding with advanced nigrostriatal dysfunction and the point at which clinical diagnosis is usually established. By this stage, a large proportion of dopaminergic neurodegeneration has already occurred, constraining the potential impact of disease-modifying or neuroprotective interventions. Braak neuropathological stages are schematically shown to contextualize canonical patterns of α-synuclein propagation, while acknowledging substantial biological heterogeneity, genetic divergence, and incomplete clinicopathological concordance. Risk factors and factors associated with relative resilience are depicted as acting across the disease continuum, highlighting that vulnerability and resilience are shaped long before clinical recognition. The indicated window emphasizes the theoretical opportunity for neuroprotective intervention, underscoring a central challenge in PD: the persistent misalignment between the timing of neurodegeneration, the emergence of clinically actionable phenotypes, and the thresholds at which intervention is currently initiated.