Reducing Alzheimer's disease risk with SGLT2 inhibitors: From glycemic control to neuroprotection

Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2 inhibitor therapies are FDA-approved medications routinely prescribed to manage diabetes. This novel class was initially developed to address cardiovascular disorders and to reduce the risk of hypoglycemia associated with insulin-secretagogue agents. It subsequently attracted growing interest for its beneficial effects on central nervous system (CNS) disorders. However, the molecular mechanisms through which these glucose-lowering therapies mitigate cognitive decline and limit the progression of certain brain degenerative diseases remain largely unexplored. Consequently, the neuroscientific community needs further studies that gather, analyze, and critically discuss the available mechanistic evidence regarding the neuroprotective effects of SGLT2 inhibitors. This review aims to critically examine the most relevant published findings, both in vitro and in vivo, as well as human studies evaluating the impact of SGLT2 inhibitors exposure on Alzheimer's disease (AD). It seeks to integrate the current understanding of their beneficial effects at the molecular level and their role in addressing the pathophysiology and neuropathology of AD. These insights will help extend our knowledge of how SGLT2 inhibitor therapies are associated with reduced risk of dementia and thus shed light on the link between diabetes and AD.