From Anesthetic to Neuroprotector: Multi-Omics Reveals Ketamine’s Previously Unexplored Neuroprotective Role in Alzheimer’s Disease

Introduction: Alzheimer's disease (AD) lacks effective biomarkers and diseasemodifying therapies. This study explored transcriptomic dysregulation, immune-metabolic crosstalk, and drug repurposing opportunities in AD. Methods: Transcriptomic datasets (GSE109887, GSE5281) were harmonized using batch correction. Differentially expressed genes (DEGs) were identified, and Weighted Gene Co-Expression Network Analysis (WGCNA) prioritized AD-associated modules. Machine learning (RF+LDA) validated diagnostic genes across external cohorts (GSE29378, GSE122063). Functional enrichment, immune infiltration (CIBERSORT), single-cell analysis (AlzData), Mendelian randomization (MR), and drug repurposing (DSigDB/CB-Dock2) were employed. Results: WGCNA identified the yellow module as most AD-relevant. Machine learning prioritized 15 diagnostic genes (e.g., CASP6, LDHA, CHRM1), achieving AUCs of 0.941 (training) and 0.715- 0.910 (validation). Single-cell analysis confirmed their dysregulation in AD brains. MR revealed FIBP as a protective factor, inversely linked to AD risk. Immune profiling showed increased naive B cells and M1 macrophages in AD. Ketamine exhibited the highest drug enrichment (fold enrichment = 49.12), with strong binding to CASP6 (−5.3 kcal/mol), CHRM1 (−7.8 kcal/mol), and LDHA (−6.7 kcal/mol). Discussion: CASP6, LDHA, and CHRM1 underpin immune-metabolic dysregulation in AD. Ketamine targets these genes, suggesting therapeutic potential. FIBP’s protective role and naive B-cell shifts offer novel mechanistic insights. result: WGCNA identified the yellow module as most AD-relevant. Machine learning prioritized 15 diagnostic genes (e.g., CASP6, LDHA, CHRM1), achieving AUCs of 0.941 (training) and 0.715–0.910 (validation). Single-cell analysis confirmed consistent dysregulation of these genes across AD brain regions. MR revealed FIBP as a protective factor, inversely linked to AD risk. Immune profiling showed increased naive B cells and M1 macrophages in AD. Drug enrichment highlighted ketamine (fold enrichment = 49.12) with strong binding affinities to CASP6 (-5.3 kcal/mol), CHRM1 (-7.8 kcal/mol), and LDHA (-6.7 kcal/mol). Conclusion: This integrative study identifies robust diagnostic biomarkers and nominates ketamine for repurposing in AD. Experimental validation of ketamine’s neuroprotective effects and FIBP’s role is warranted.