Causal association between plasma metabolites and neurodegenerative diseases

Background: Establishing causal relationships between metabolic biomarkers and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is a challenge faced by observational studies. In this study, our aim was to investigate the causal associations between plasma metabolites and neurodegenerative diseases using Mendelian Randomization (MR) methods. Methods: We utilized genetic associations with 1400 plasma metabolic traits as exposures. We used large-scale genome-wide association study (GWAS) summary statistics for AD and PD as our discovery datasets. For validation, we performed repeated analyses using different GWAS datasets. The main statistical method employed was inverse variance-weighted (IVW). We also conducted enrichment pathway analysis for IVW-identified metabolites. Results: In the discovered dataset, there are a total of 69 metabolites (36 negatively, 33 positively) potentially associated with AD, and 47 metabolites (24 negatively, 23 positively) potentially associated with PD. Among these, 4 significant metabolites overlap with significant metabolites (P-IVW < 0.05)in the validation dataset for AD, and 1 metabolite overlaps with significant metabolites in the validation dataset for PD. Three metabolites serve as common potential metabolic markers for both AD and PD, including Tryptophan betaine, Palmitoleoylcarnitine (C16:1), and X-23655 levels. Further pathway enrichment analysis suggests that the SLC-mediated transmembrane transport pathway, involving tryptophan betaine and carnitine metabolites, may represent potential intervention targets for treating AD and PD. Conclusion: This study offers novel insights into the causal effects of plasma metabolites on degenerative diseases through the integration of genomics and metabolomics. The identification of metabolites and metabolic pathways linked to AD and PD enhances our comprehension of the underlying biological mechanisms and presents promising targets for future therapeutic interventions in AD and PD.