Association Between Different Types of Lipids and Alzheimer's Disease, Parkinson's Disease, and Epilepsy: A Mendelian Randomization and Bioinformatics Analysis.

Background: With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders.

Methods: Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis.

Results: The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP.

Conclusion: This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.