The ketogenic diet in Parkinson's disease: mechanisms, evidence, and clinical practice

Parkinson's disease (PD) represents the second most common neurodegenerative disorder across the globe. Conventional levodopa treatment can only alleviate disease-related symptoms and fails to restrain the progressive deterioration of PD. Metabolic abnormalities that mainly include mitochondrial dysfunction, cerebral insulin resistance, and disrupted energy homeostasis have been proven to be core pathogenic factors of PD, which makes metabolic interventions a promising therapeutic strategy for disease management. The ketogenic diet (KD) is a high-fat, low-carbohydrate dietary regimen that can induce endogenous ketone synthesis, and it exerts multi-dimensional neuroprotective effects on PD. This review systematically elaborates the potential molecular mechanisms through which KD protects against PD, which covers the improvement of cerebral energy metabolism, antioxidant and anti-apoptotic activities, suppression of neuroinflammation, regulation of α-synuclein (α-syn) pathological aggregation, and modulation of gut-brain axis. We comprehensively synthesize preclinical research evidence from cell and animal models as well as clinical data across case reports, pilot studies and randomized controlled trials, and we summarize critical clinical application principles that include dietary protocols selection, patient screening criteria, safety monitoring indicators and diet-drug interactions. Although KD intervention appears to improve selected motor and non-motor symptoms of PD, the current evidence remains preliminary, with prominent limitations including inconsistent trial outcomes, high dropout rates, heterogeneous dietary schemes and insufficient exploration of multi-omics. The inconsistent clinical outcomes, high trial dropout rates, heterogeneous dietary protocols, limited biomarker validation, and insufficient long-term efficacy and safety data limit its widespread clinical application. Large-scale, well-controlled clinical trials with standardized ketosis monitoring, disease-progression biomarkers, and extended follow-up are therefore required to verify the translational application value of KD in PD management.