Background: Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.
Objective: This study investigates the correlation between immune-related plasma proteins and the risk of NDs by integrating genome-wide association study (GWAS) data for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) with plasma proteome analysis.
Methods: By analyzing GWAS data for 4907 immune-related plasma proteins, this research evaluates the direct impact of plasma proteins on the risk of four NDs: AD, PD, ALS, and MS. Additionally, the study conducts an analysis of protein expression levels using single-cell RNA sequencing data.
Results: We have identified plasma proteins that are closely associated with the risk of NDs. Using stringent criteria, we identified 88 proteins associated with AD, 115 with PD, 100 with ALS, and 87 with MS. Additionally, single-cell sequencing analyzed the protein expression and its distribution within different cell types in the brain.
Conclusions: Our research has demonstrated that plasma proteins may contribute to the risk of NDs, and it has also provided concrete evidence linking genetic susceptibility for these diseases to immune mechanisms. Furthermore, we found that specific proteins influence genetic variations linked to NDs risk via plasma-mediated regulation, emphasizing the importance of interactions between the brain and circulatory system.
Keywords: Mendelian randomization; Neurodegenerative diseases; causality; plasma proteins; snRNA-seq.