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

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) or plasminogen activator inhibitor-1 (PAI-1). At present, the causal relationship is not clear. Therefore, this study intended to explore the relationship between plasminogen activators and their inhibitors with Alzheimer's disease through the Mendelian randomization method, so as to provide a 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. Inverse-variance weighted (IVW), Mendelian randomization-Egger (MR-Egger), weighted-median, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and Mendelian randomization-robust adjusted profile score (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 odds ratios [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.