# Brain and CSF Alzheimer's Biomarkers Are Associated with SERPINE1 Gene Expression
## 4 Discussion  
SERPINE1 was originally identified as a negative regulator of fibrinolysis by preventing the dissolution of blood clots [17]. Increased concentration of SERPINE1 in plasma can cause venous thrombosis and myocardial infarction [18]. More recently, myocardial infarction was proposed to be a predisposing factor for AD development [19]. Mounting evidence suggests that the ageing of the neurovasculature is a critical determinant of brain ageing and AD risk [20]. In neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration, plasma levels of SERPINE1 were found in higher concentrations [21,22]. These associations prompted us to examine SERPINE1 neurobiology throughout AD spectrum, i.e., before and after AD onset in multiple living and autopsied cohorts. Using autopsy-confirmed AD brains, we showed that cortical _SERPINE1_ mRNA levels are significantly higher compared to CTL brains (Figure 1B, \(p\) = 0.03). This association is also slightly affected by both _APOE4_ status and gender. These results are consistent with the previous literature reporting the upregulation of _SERPINE1_ mRNA levels in the superior frontal gyrus, entorhinal cortex and hippocampus of AD subjects compared to age-matched controls [8]. Only AD patients without _APOE4_ in the ADNI CSF cohort showed increased SERPINE1 (Figure S1). Plasmin, when inhibited by SERPINE1, is known to facilitate the degradation of A\(\beta\) fibrils [5] and is found in low concentrations in AD versus control brains [6]. In this context, it was tempting to propose that SERPINE1 could affect senile plaque density in a regional and concentration-dependent manner. In Figure 1C, we found such interaction at a trend level but only in _APOE4_-negative subjects. In the same vein, we examined the influence of _SERPINE1_ on neurofibrillary tangles density and found a weak correlation between the two, but only in males (Figure 1F). Using a replication cohort from the Mayo brain bank with a larger sample size, we investigated the influence of _SERPINE1_ on tangle spreading using Braak staging [23]. A positive association was found between cortical _SERPINE1_ mRNA levels and Braak stages in females only (Figure 2B). It is of note that the proportion of females was higher in the AD group compared to non-AD, which could explain, at least in part, those results. Nevertheless, a positive correlation with both NFT (Figure 1F) and Braak (Figure 2) suggests a possible influence on Tau metabolism and/or deposition. To determine if SERPINE1 could be used as an early, presymptomatic, AD biomarker, we turned to the PREVENT-AD cohort, comprising asymptomatic \"at-risk\" individuals. Figure 3 shows strong correlations between CSF SERPINE1 protein levels and pTau181 and tTau, especially in females and _APOE4_-negative subjects (see also Figure S2 for ADNI results). These results are consistent with the tangles/_SERPINE1_ association described earlier in fully established AD cases. Note that for A\(\beta\), the expected negative correlation with _SERPINE1_ was not established (Figures 3A and S2A). Using proteomic quantitative trait loci analysis, we identified genome-wide and locus-wide significant (naturally occurring) polymorphisms that display significant association with SERPINE1 protein levels in the CSF of our asymptomatic cohort of subjects (Supplemental Figures S4 and S5). The two variants that modulates CSF SERPINE1 concentration, rs17705051 (_VAT1L_) and rs6092 (_SERPINE1_) failed to affect AD risk levels when assessed in our three distinct cohorts (Table 2). Using the larger publicly available IGAP GWAS database ([[https://www.nature.com/articles/ng.2802](https://www.nature.com/articles/ng.2802)]([https://www.nature.com/articles/ng.2802](https://www.nature.com/articles/ng.2802)), accessed on 1 November 2024), we performed additional screening for AD risk in this large dataset (\(n\) = 74,046) and found no significant genome-wide association with sporadic AD for rs17705051 (\(p\) = 0.1779) nor for rs6092 (\(p\) = 0.002).