Abstract Background: Alzheimer’s disease (AD) is characterized by progressive neurodegeneration in regionally vulnerable brain areas, yet molecular insights into early pathogenic mechanisms remain limited. Methods: We conducted a meta-analysis of transcriptomic datasets from brain regions affected in early-to-moderate AD – including entorhinal cortex, CA1 hippocampus, angular gyrus, and frontal cortex synaptoneurosomes – using data from seven mRNA and one microRNA (miRNA) microarray studies (GSE16759, GSE110226, GSE37264, GSE26972, GSE36980, GSE37263, GSE39420, and GSE157239). Preprocessing included background correction, log 2 transformation, quantile normalization, and batch correction via ComBat. Differentially expressed features were defined as false discovery rate <0.05 and | logFC| ≥ 1.23 (genes) or ≥ 2 (miRNAs). Results: We identified 172 differentially expressed genes (122 upregulated and 50 downregulated) and 82 significant miRNAs. Hub genes included Inositol-trisphosphate 3-kinase B ( ITPKB ), Synaptotagmin 1, Dystrobrevin alpha ( DTNA ), X Inactive Specific Transcript, and Regulator of G protein signaling 4 ( RGS4 ). Functional enrichment highlighted calcium signaling, synaptic failure, and neuroinflammation. Notably, hsa-miR-30d-5p was predicted to target both ITPKB and DTNA , suggesting a regulatory axis linking miRNA dysregulation to calcium dyshomeostasis. Receiver operating characteristic analysis revealed that only RGS4 showed moderate discriminative capacity (area under the curve AUC =0.70), while other hub genes (e.g., ITPKB , AUC = 0.40) exhibited below-chance performance, underscoring the limitations of single-gene classifiers in postmortem tissue. Conclusion: This study provides mechanistic hypotheses – rather than diagnostic biomarkers – by uncovering region-specific, miRNA-mediated regulatory networks in AD-affected brain tissues. Future validation in accessible biofluids is essential before clinical translation.
Jaberi et al. (2026) studied this question.