# Brain and CSF Alzheimer's Biomarkers Are Associated with SERPINE1 Gene Expression
## 4 Discussion
A previous study involving the ADNI cohort identified an intronic SNP in _VATIL_ in association with cognitive decline measured by ADAS-cog [24]. In our asymptomatic cohort, the SNP affecting CSF SERPINE1 protein levels was found downstream of the _VATIL_ gene. Further studies will be necessary to establish the link between VAT1L and SERPINE1. The cis-acting SNP rs6092 is a coding SNP associated with impaired secretion of SERPINE1 and hemorrhage problem [25]. Other SNPs in _SERPINE1_ were shown to affect AD risk [26; 27]. In the early stages of AD, there is a swift degeneration of hippocampal tissue, which can be measured by magnetic resonance imaging [28]. In the PREVENT-AD cohort, we show that CSF SERPINE1 correlates inversely with hippocampus volume, particularly in females and _APOE4_-negative subjects (Figure 4 and Supplemental Figure S3 for ADNI results). These results suggest that in the absence of symptoms in at-risk individuals, hippocampal loss can be predicted by the presence of high levels of SERPINE1 in the CSF. In preclinical stages of AD, changes in synaptic proteins were shown to precede CSF markers of neurodegeneration [29]. Increased concentrations of the presynaptic markers GAP43, SNAP25 and SYT1 were observed in the CSF during neurodegeneration [12; 30; 31]. In the asymptomatic PREVENT-AD cohort, we found that CSF SERPINE1 positively correlates with those three pre-synaptic markers in both _APOE4_-negative and -positive subjects (Figure 5, upper panels) as well as in all females (Figure 5, lower panels). Previous studies suggest that cognitive deficit is more closely associated with abnormalities in synaptic structure and function than with the quantity of plaques and tangles [21; 32]. Our research indicates a connection between SERPINE1 and the advancement of AD, most notably in the disease's asymptomatic period. More specifically, SERPINE1 correlates with early signs of neurodegeneration, namely with elevated levels of tTau and a reduction in hippocampus volume. In parallel, SERPINE1 is strongly linked to pTau181 tau alterations in the CSF and the presence of high concentration of synaptic markers. Over time, when AD pathology sets in, _SERPINE1_ mRNA levels are elevated and show a weak correlation with plaques and NFT densities but a more significant correlation with tangle spreading monitored by Braak staging. Our results support the notion that SERPINE1 can be used as an early biomarker for the detection of AD-associated pathological changes in asymptomatic subjects with a parental history of AD. Interestingly, most of the significant results are observed in _APOE4_-negative subjects, who are usually at lower risk of developing AD. SERPINE1's strongest association is with tau pathology, a surprising finding considering the plasminogen activator system's role in A\(\beta\) fibril degradation. SERPINE1's biological network includes proteins such as PLAT, TP53 and IL6 that could possibly have an indirect effect on Tau phosphorylation via the main kinase GSK3B (Figure S6). Further investigations are necessary to determine if the pharmacodynamic of SERPINE1 could be used to modulate disease progression. **Supplementary Materials:** The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/genes16070818/s1](https://www.mdpi.com/article/10.3390/genes16070818/s1)]([https://www.mdpi.com/article/10.3390/genes16070818/s1](https://www.mdpi.com/article/10.3390/genes16070818/s1)). Figure S1: CSF SERPINE1 levels according to diagnostics in the ADNI cohort; Figure S2: CSF SERPINE1 levels compared to AD biomarkers in the ADNI cohort; Figure S3: CSF SERPINE1 levels compared to hippocampus volume in the ADNI cohort; Figure S4: Genome-wide association with CSF SERPINE1 protein levels in the PREVENT-AD cohort; Figure S5: Locus-wide association with CSF SERPINE1 protein levels in the ADNI cohort; Figure S6: SERPINE1 string network. **Author Contributions:** Conceptualization, C.P. and J.P.; methodology, C.P., H.Z., K.B., S.V. and J.P.; formal analysis, C.P.