Biomarkers.

Background: Alzheimer's disease (AD) is the most common form of dementia, characterized by cognitive impairment and memory loss. Previous studies have demonstrated that plasminogen, a key molecule in the fibrinolytic system, is implicated in the pathophysiology of AD. However, it is yet unknown whether the relationship between blood plasminogen and AD is causal.

Methods: Leveraging instrumental variables (IV) from genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between plasminogen levels and AD risk. Summary-level data on blood plasminogen levels was from a GWAS on human blood plasma proteome, and summary statistics on AD were from the International Genomics of Alzheimer's Project (IGAP, N=63,926). Inverse variance weighted (IVW) was used as the primary approach to calculate the estimate, which was further validated using the following sensitivity analyses, including MR-Egger, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), weighted median, simple mode, and weighted mode methods. Additionally, tests for pleiotropy and heterogeneity were conducted to further assess the stability of the MR estimates.

Results: Using the IVW approach, our findings revealed a significant association between higher genetically determined plasminogen levels and an increased risk of AD (odds ratio [OR] = 1.10, 95%CI = 1.04-1.16, P =0.008), which was further confirmed in sensitivity analyses (Figure 1A). The leave-one-out analysis plot revealed that the causal estimate between plasminogen levels and AD was not driven by any single instrumental variable (Figure 1B). The findings from the MR-Egger intercept test and Cochran's Q test revealed an absence of significant directional horizontal pleiotropy and heterogeneity, suggesting a high level of stability in the current MR study.

Conclusions: According to our research, there is a direct causal link between increased circulating plasminogen levels and a higher risk of AD. Further studies are warranted to evaluate the underlying mechanism of our findings.