# Brain and CSF Alzheimer's Biomarkers Are Associated with SERPINE1 Gene Expression
## 3 Results
### SERPINE1 Protein Levels Correlate Positively with Synaptic Markers  
Figure 5 shows significant positive correlations between CSF SERPINE1 protein levels and three synaptic markers: GAP43 (Figure 5A, _APOE4_ neg, \(p=0.016\)), SNAP25 (Figure 5B, _APOE4_ neg, \(p=0.03\); _APOE4_ pos, \(p=0.013\)) and SYT1 (Figure 5C, _APOE4_ neg, \(p=0.015\)). Figure 5 (lower panels) reveals significant gender-specific correlations between SERPINE1 and GAP43 (Figure 5A, females, \(p=0.002\)), SNAP25 (Figure 5B, females, \(p=0.0036\)) and SYT1 (Figure 5C, males, \(p=0.05\); females, \(p=0.009\)). Quantitative Trait Loci Analysis of CSF SERPINE1 Levels Identifiers Naturally Occurring Polymorphisms in the SERPINE1 and VATL Genes  
Using trans-pQTL analysis, we identified a genome-wide significant polymorphism (rs17705051 downstream of the _VAT1L_ gene, Supplemental Figure S4) that affects SERPINE1 levels in the CSF of cognitively unaffected PREVENT-AD subjects. Rs6092, a coding SNP, was identified as the most significant cis-pQTL influencing polymorphism using CSF  
Figure 2: _SERPINE1_ mRNA levels compared to Braak stages. _SERPINE1_ mRNA levels were measured using RNAseq in 193 frontal cortices from the Mayo clinic cohort and contrasted with _APOE4_ and gender. (**A**) In _APOE4_-negative subjects, correlations were found at a trend level between _SERPINE1_ mRNA levels and Braak stages (\(p=0.05\)). (**B**) In females only, _SERPINE1_ mRNA levels increased in relation to Braak stages (\(p=0.0008\)). SERPINE1 protein levels in the ADNI cohort (Supplemental Figure S5). While the presence of these variants has no impact on AD risk levels (Table 2) in three cohorts (ADNI, MAYO, DBCBB), they significantly affect protein concentrations of SERPINE1 in the PREVENT-AD and ADNI cohorts and the mRNA levels in the MAYO cohort. As for AD biomarkers, only the presymptomatic PREVENT-AD cohort display significant association between the vesicle amine transport 1 like (_VATIL_) variant and pTau181 (\(p\) = 0.006) as well as total tau levels in the CSF (\(p\) = 0.005). \begin{table}
\begin{tabular}{c c c c c c c c c} \hline \hline \multirow{2}{*}{**SNP**} & \multirow{2}{*}{**Cohort**} & **Freq** & **CTL** & **Freq AD** & **CTL vs. AD** & **SERPINE1 QTL** & **A\(\beta\)42** & **SP**Tau181 CSF** & **tTau CSF** \\ \cline{3-10}  & & PREVENT-AD & 0.05 & - & - & \(p\) = 5 \(\times\) 10\({}^{-8}\) (CSF) & \(p\) = 0.421 & \(p\) = 6 \(\times\) 10\({}^{-3}\) & \(p\) = 5 \(\times\) 10\({}^{-3}\) \\ \cline{2-10}  & ADNI & 0.04 & 0.04 & \(p\) = 0.801 & \(p\) = 0.654 (CSF) & \(p\) = 0.642 & \(p\) = 0.663 & \(p\) = 0.629 \\ \cline{2-10}  & DBCBB & 0.08 & 0.08 & \(p\) = 0.972 & \(p\) = 0.420 (Brain) & & & \\ \cline{2-10}  & MAYO & 0.04 & 0.05 & \(p\) = 0.703 & \(p\) = 0.413 (Brain) & & & \\ \hline \multirow{4}{*}{rs6092} & PREVENT-AD & 0.12 & - & - & \(p\) = 2.5 \(\times\) 10\({}^{-2}\) (CSF) & \(p\) = 0.067 & \(p\) = 0.674 & \(p\) = 0.870 \\ \cline{2-10}  & ADNI & 0.09 & 0.12 & \(p\) = 0.537 & \(p\) = 7 \(\times\) 10\({}^{-4}\) (CSF) & \(p\) = 0.322 & \(p\) = 0.461 & \(p\) = 0.381 \\ \cline{2-10}  & DBCBB & 0.13 & 0.22 & \(p\) = 0.184 & \(p\) = 0.792 (Brain) & & & \\ \cline{2-10}  & MAYO & 0.14 & 0.11 & \(p\) = 0.311 & \(p\) = 4.1 \(\times\) 10\({}^{-2}\) (Brain) & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: _VATIL_ and _SERPINE1_ polymorphisms. Figure 3: CSF SERPINE1 protein levels compared to A\(\beta\), pTau and tTau. CSF SERPINE1 levels were measured with the help of OLINK technology in 125 CSF samples from the PREVENT-AD cohort. (**A**) In females only, SERPINE1 protein levels were significantly positively correlated with CSF A\(\beta\) (\(p\) = 0.01). (**B**) In _APOE4_-negative and -positive, as well as in female, subjects, a significant positive correlation was found between SERPINE1 protein levels and CSF pTau (\(p\) = 0.0012, \(p\) = 0.01 and \(p\) = 0.0002, respectively).