SGLT2 Inhibitors in Alzheimer's Disease: Biochemical Insights and Therapeutic Potential
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed as antidiabetic agents, have recently gained attention for their potential role in modulating processes relevant to Alzheimer's disease (AD). Preclinical studies suggest that they may influence key mechanisms involved in AD. However, available clinical studies, mainly retrospective and focused on diabetic populations, provide insufficient clarity on whether these effects extend to broader, non-diabetic groups. The heterogeneity of neurodegenerative diseases, which differ in inflammatory and proteotoxic mechanisms, further highlights the need for disease-specific investigations. This review examines mechanistic pathways through which SGLT2 inhibition may influence AD progression and evaluates current clinical evidence, aiming to identify key knowledge gaps and guide future research. This review summarises the latest evidence from the literature, focusing on preclinical experiments, translational studies and early clinical observations. The search focused on pathways related to microglial and astrocytic activation, oxidative stress, metabolic remodeling, neuronal survival, and amyloid and tau dynamics. Accumulating data indicate that SGLT2 inhibitors exert multifaceted actions relevant to AD pathology, including reduced neuroinflammation and oxidative stress, improved mitochondrial and insulin signaling, as well as decreased amyloid deposition and tau hyperphosphorylation. Additionally, SGLT2 inhibition may…
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