ObjectivesObservational studies have shown that plasma lipids are associated with the development of neurodegenerative diseases (NDD), but the causal relationship is unclear. This study investigated the causal relationship between 179 liposomes and NDD using a two-sample Mendelian randomization (MR). MethodA two-sample Mendelian randomization method was used to comprehensively analyze the causal relationship between liposomes and major NDD such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The two sample software package and Phenoscanner database were used to screen for appropriate instrumental variables(TV). In this study, inverse variance weighting (IVW) was used as the primary measure of MR analysis, and various sensitivity tests were performed. ResultsMR-IVW results showed that phosphatidylethanolamine (PE) (OR=0.90, 95%CI 0.83 to 0.99, P=0.03), phosphatidylcholine (PC) (OR=0.92, 95%CI 0.85 to 0.99, P=0.02) and phosphatidylinositol (PI) (OR=0.90, 95%CI 0.83 to 0.99, P=0.03) were protective factors for AD. Sterol ester (OR=1.18, 95%CI 1.04 to 1.34, P=0.01) and cholesterol (OR=1.26, 95%CI 1.02 to 1.56, P=0.03) increased the risk of PD. PE (OR=0.79, 95%CI 0.64 to 0.98, P=0.03) and PC (OR=0.83, 95%CI 0.69 to 0.98, P=0.03) reduced the risk of PD. Diacylglycerol (DAG) (OR=1.24, 95%CI 1.01 to 1.54, P=0.04) and sphingomyelin (SM) (OR=1.13, 95%CI 1.08 to 1.58, P=0.01) were the risk factors for MS. PI (OR=0.77, 95%CI 0.62 to 0.95, P=0.02) and PC (OR=0.74, 95%CI 0.88 to 0.95, P=0.02) were protective factors for MS. PI (OR=1.02, 95%CI 1.01 to 1.04, P=0.02) and triglyceride (TG) (OR=1.03, 95%CI 1.01 to 1.05, P=0.02) increased the risk of ALS, PC (OR=0.98, 95%CI 0.97 to 0.99, P=0.03) decreased the risk of ALS. ConclusionsThere is a causal relationship between sterol ester, cholesterol, PC, PE, PI, DAG, SM, TG and different NDD, which will provide theoretical basis and support for further clinical studies.