Figure 5All data have been adjusted for age, gender and other latent covariates for downstream eigenvalue calculation. A. Eigen value showing the increased expression of the 3-microRNA signature in blood plasma samples of age matched MCI (n = 23) patients compared to controls (n = 27). B. Expression of 3-microRNA signature is increased in PAXgene blood samples of MCI patients (n=71) compared to controls (n=65) from the DELCODE cohort. C. Clustering of eigen-expression identifies two expression clusters in MCI patients based on elbow method of detecting optimum number of clusters. D. Patients representing the cluster with higher expression of 3-miR eigenvalue shows negative correlation with their weighted cognitive score (cor = 0.444, p = 0.004). In contrast, patients with low expression of 3-miR signature did not show significant correlation with the cognitive score (p=0.73). E. Eigen value showing the expression the 3-microRNA signature in MCI patients for those the follow up diagnostics data assessed 2 years after were available. 15% of these MCI patients developed Alzheimer´s disease (AD), while the rest 85% patients remained with MCI (stable MCI). The boxplot depicts the increased expression levels of 3-miR signature in patients who converted to AD (n=8) compared to those that had stable MCI (n=47). F. Increased expression of 3-microRNA signature in cerebrospinal fluid (CSF) of MCI patients (n = 9) compared to controls (n = 26). Wilcoxon-rank test, P value is given on the corresponding panel. In the boxplots in (A, B, E, F), the center line indicates the median, while the upper and lower lines represent the 75th and 25th percentiles, respectively. The whiskers represent the smallest and largest values in the 1.5× interquartile range. G. Human bioengineered neuronal organoids (BENOs) were treated at DIV 60 with the 3-miR-mix or corresponding controls for 24 hours and RNAseq was performed from prepared RNA. Volcano plot displays the significant deregulated genes in BENOs after over-expressing the 3-miR-mix (FDR<0.05). H. Gene ontology shows top 10 significant up- and downregulated processes based on the differentially expressed genes. X-axis represents the -log10 of adjusted p value. I. A meta-analysis for 3-microRNA signature was performed across different datasets. The upper part shows the human datasets, while the lower part shows the investigated mouse datasets. In addition to the datasets presented in our study we also employed cortical smallRNAome data (GSE8998) from a fronto-temporal dementia (FTLD) mouse model at a presymptomatic state (Swarup et al, 2018). Standardized mean difference (SMD) of zero indicates no effect. Deviation from zero would indicate either an increase or a decrease of the eigen-expression for the 3-microRNA signature. Asterisks represent the adjusted p value across studies (length = 15). *P<0.05, **P<0.01, ***P<0.001. Standardized mean difference (SMD) of 3-microRNA signature is given along with the corresponding lower and upper interval. A large pooled standardized mean difference (1.44) for 3-microRNA signature was observed across species and the overall effect in both species (Z = 5.33) was highly significant (P<0.001).