Using Mendelian randomization in large European samples, the study implicates specific plasma lipids (e.g., triacylglycerol and phosphatidylcholine as protective; sphingomyelin as pathogenic), two trace elements (selenium protective; an unexpected iridium signal), and CSF metabolites (including…

Provides genetically supported, actionable leads linking lipid metabolism and specific CSF metabolites to PD risk and progression—highlighting biomarkers and candidate intervention targets (e.g., phosphatidylcholine, uridine, selenium) that can be prioritized for experimental validation and…

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms such as dementia, depression, and anxiety. Despite numerous studies on the prevention and treatment of PD, the causal relationships between plasma lipids, trace elements, cerebrospinal fluid (CSF) metabolites and PD remain unclear. METHODS: This study employed Mendelian Randomization (MR) analysis using large European population samples to examine these relationships. RESULTS: We identified 17 lipid phenotypes, 2 trace elements (Selenium and Iridium), and 8 CSF metabolites that have a significant causal association with PD. Lipid phenotypes such as Triacylglycerol and Phosphatidylcholine were found to be protective against PD, while Sphingomyelin and other lipid types were identified as pathogenic. Selenium has been shown to have a protective effect, while Iridium is negatively associated with the progression of PD, suggesting a different role than other heavy metals.Our mediation analysis also revealed that these lipids could influence PD through their effects on CSF metabolites. For instance, Phosphatidylcholine and Uridine were found to protect neurons and improve PD prognosis, whereas no consistent mediation effect was observed for trace elements. CONCLUSION: Overall, our results provide new insights into the complex relationships between plasma lipids, trace elements and CSF metabolites and PD. These results offer potential pathways for future research and provide valuable information for the prevention and treatment of PD.