Integrative transcriptomic and regulatory network analysis reveals associations of seven proposed risk genes with immune-related molecular features in Alzheimer's disease

have been identified, but their associations with the immune microenvironment (IME) remain unclear.ObjectiveThis study investigates associations between these genes and the neuroimmune landscape in AD.MethodsIntegrative transcriptomic and regulatory network analysis was performed using the GSE53697 dataset (9 AD and 8 control samples) from the GEO. Immune cell enrichment scores and pathway activity were evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA), and enriched pathways were identified through Gene Set Enrichment Analysis (GSEA). Upstream regulatory associations were explored by constructing miRNA-mRNA and transcription factor regulatory networks, and correlations between the risk genes and established AD-related genes were assessed using public databases.ResultsAD samples showed immune dysregulation, including reduced dendritic cell ssGSEA scores. All seven risk genes correlated with immune cell subsets and immunomodulatory molecules. Enrichment analysis revealed inflammatory pathways including NF-κB, IL-17, TNF, MAPK, and Notch, suggesting potential links to neuroinflammation and neuronal signaling disruption. Upstream analysis identified 85 miRNAs and several transcription factor motifs annotated to HOXA13, ESRRA, and SNAI1/2/3. Correlation analysis further revealed associations between risk genes and AD-related genes, placing these genes within established AD pathological networks in an exploratory manner.ConclusionsThis exploratory study provides insights into how AD risk genes are associated with the IME and may be linked to neuroinflammatory pathways and neuronal function, providing hypotheses for future studies of immune-genetic crosstalk in AD pathogenesis.