Association of VTN Genotype with Plasminogen Activator Inhibitor-1 Activity in Late-Onset Alzheimer's Disease

Late-onset Alzheimer's disease (LOAD) is a multifactorial neurodegenerative disorder involving the interaction of genetic and environmental factors. Dysregulation of the fibrinolytic system, particularly an increase in plasminogen activator inhibitor-1 (PAI-1) levels, may contribute to Alzheimer's pathology. Vitronectin (VTN) regulates fibrinolysis by stabilizing PAI-1. This study investigated the relationships between plasma PAI-1 activity and VTN, SERPINE1 (PAI-1), and APOE gene variants in nineteen LOAD patients (>65 years) and ten cognitively normal age-matched control groups.

Targeted next-generation sequencing was used to analyze the VTN, APOE, and SERPINE1 genes in 19 LOAD patients and ten controls. Additionally, plasma PAI-1 activity was measured in both groups.

Plasma PAI-1 activity was statistically significantly higher in LOAD patients compared to controls (p = 0.04). Targeted next-generation sequencing results showed that VTN 5'-UTR variants (rs7212814, rs1555584131, rs71135830, and rs11437594) were found in all patients and observed in 20% of controls (p = 0.0001). The VTN rs704 variant was detected in 84% of patients and 29% of controls (p = 0.001). VTN 5'-UTR variants showed Spearman correlation with PAI-1 activity (r = 1.0; p < 0.0001). SERPINE1 3'-UTR variants (rs11178, rs41423845) were found to be associated with the disease (p = 0.027; p = 0.0001). The APOEε3/ε4 genotype was present in 52.6% of patients and was not associated with PAI-1 activity. VTN variants showed an association with LOAD.

These findings suggest that VTN variants may contribute to LOAD pathogenesis by affecting PAI-1 and leading to fibrinolytic system dysregulation.