Integrated transcriptomic analysis of the temporal cortex identifies CRH and GAD2 as neuropathological markers and...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by complex neuroimmune interactions. Identifying reliable neuropathological markers and understanding immune cell infiltration in the brain are essential for improving our understanding of AD pathology. We integrated four temporal cortex gene expression datasets from the GEO database (GSE36980, GSE37263, GSE118553, GSE122063). Differentially expressed genes (DEGs) were identified using RobustRankAggreg (RRA) and batch correction. Functional enrichment was analyzed via GO and KEGG, and hub genes were identified through protein-protein interaction networks and comparative intersection analysis. Diagnostic performance was evaluated using ROC curves, and immune cell infiltration was profiled with CIBERSORT, with significant immune subsets identified via Wilcoxon tests and LASSO regression. Analysis revealed 98 robust DEGs, prominently enriched in pathways related to synaptic transmission and neuroactive ligand-receptor interactions. Two hub genes, CRH and GAD2, were identified and validated as being significantly downregulated in AD. ROC analysis affirmed their high discriminatory value (AUC ≥ 0.7), with a combined model demonstrating good performance. Immune infiltration profiling in the AD temporal cortex uncovered significant alterations in six immune cell populations: M2 macrophages, activated dendritic cells, and resting mast cells were increased, while plasma cells, regulatory T cells (Tregs), and activated NK cells were decreased. However, no significant correlation was found between the expression of CRH/GAD2 and these immune cell alterations. CRH and GAD2 are potential neuropathological markers for AD. The distinct immune infiltration patterns observed highlight the involvement of both innate and adaptive immunity in AD pathogenesis, offering new insights for understanding AD pathology and informing future therapeutic strategies. The lack of direct correlation suggests that neuronal gene dysregulation and immune alterations may represent parallel or independently regulated pathological dimensions in AD.