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Abstract

Introduction

Alzheimer's disease (AD) lacks effective biomarkers and disease-modifying 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 (., , , ), 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 high 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.

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.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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From Anesthetic to Neuroprotector: Multi-Omics Reveals Ketamine’s Previously Unexplored Neuroprotective Role in Alzheimer’s Disease
Bentham Science Publishers ; https://doi.org/10.2174/0118715273396403250825131703
/content/journals/cnsnddt/10.2174/0118715273396403250825131703
/content/journals/cnsnddt/10.2174/0118715273396403250825131703
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  • Article Type:     Research Article
Keywords: transcriptomics ; ketamine ; WGCNA ; drug repurposing ; Mendelian randomization ; machine learning ; FIBP ; Alzheimer’s disease ; immune infiltration

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