Causal association of plasminogen activators and their inhibitors with Alzheimer's disease: a Mendelian randomization study

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, and contributes to a huge burden of disease worldwide. Observational studies have found that tissue plasminogen activator (t-PA) inhibits the development of AD, but little is known about urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1). At present, the causal relationship is not clear. Therefore, this study intends to explore the relationship between plasminogen activators and their inhibitors with Alzheimer's disease through Mendelian randomization method, so as to provide reference for the prevention and control of Alzheimer's disease.To investigate causal pathways, we conducted a two-sample Mendelian randomization study using pooled statistics from genome-wide association studies. IVW, MR-Egger, Weighted-median, MR-PRESSO and MR-RAPS methods were used to evaluate the robustness of the results.In the outcome of AD (more controls excluded), the IVW effect of PAI-1 OR (95%CI) was found as follows: 1.543 (1.010-2.356), whose interval does not include 1 and P=0.0448, which suggested that PAI-1 was positively correlated with the risk of AD (more controls excluded). The IVW model, Weighted median, MR-PRESSO and MR-RAPs all showed similar results (all ORs >1), and the two outcomes were consistent.Our results showed that gene-predicted PAI-1 in Mendelian stochastic analysis was associated with an increased risk of AD.