Deciphering the neuroprotective signaling of SGLT2 inhibitors in Alzheimer's disease.

Authors

Takahiro Kamihara, Ryutah Kato, Akira Morisaki, Shinji Kaneko, Takuya Omura, Atsuya Shimizu

Published in

Journal of Alzheimer's disease : JAD. Pages 13872877261502860. Oct 30, 2026. Epub Oct 30, 2026.

Abstract

BackgroundAlzheimer's disease (AD) currently lacks fundamental curative treatments. While epidemiological evidence increasingly links sodium-glucose cotransporter 2 (SGLT2) inhibitors to reduced AD risk, the underlying molecular mechanisms remain poorly understood.ObjectiveThis study aimed to elucidate the potential molecular pathways through which SGLT2 inhibitors intervene in AD pathophysiology using a bioinformatics approach.MethodsPotential targets for empagliflozin and dapagliflozin were predicted via SwissTargetPrediction. AD-related differentially expressed genes (DEGs) were identified from a human brain dataset (GSE125583) utilizing the GREIN platform. Common genes were analyzed for functional networks (GeneMANIA/STRING) and pathway enrichment (KEGG). Hub proteins were identified using Cytoscape centrality metrics, and organ-specific expression was verified through the RefEx database.ResultsFifty-seven genes were common to SGLT2 inhibitor targets and AD DEGs. Notably, the transporters SLC5A11 and SLC2A1 were significantly upregulated in AD brains and exhibited high brain-specific expression. Pathway analysis revealed significant involvement in the MAPK and FoxO signaling pathways, which regulate apoptosis, autophagy, and oxidative stress. Key hub proteins identified included ERBB2, HSP90AA1, DPP4, and SLC2A1. It is hypothesized that SGLT2 inhibitors exert neuroprotective effects by targeting these upregulated transporters, thereby suppressing MAPK signaling and activating the FoxO pathway.ConclusionsOur findings suggest that SGLT2 inhibitors may normalize MAPK/FoxO signaling and restore cellular homeostasis in the AD brain. This study provides a potential theoretical insight for the drug repositioning of antidiabetic agents and offers key indicators for the design of future clinical and basic research in AD therapy.

PMID:
42961128
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.

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