Pathomechanisms, genetic insights, and therapeutics in diabetes-associated dementia

Abstract

Type 2 diabetes (T2DM) significantly increases the risk of dementia due to overlapping metabolic, molecular, and genetic factors. This review comprehensively analyzes the pathophysiological links between diabetes and cognitive decline, focusing on chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cerebrovascular complications. Key genetic and epigenetic contributors to diabetes-associated dementia (DAD), including variations in APOE, PICALM, SORL1, and GSK3B, are discussed. The roles of pathological proteins such as amyloid-beta (Aβ) and hyperphosphorylated tau in neurodegeneration are also highlighted. Preclinical and clinical evidence supports targeting insulin signaling pathways, oxidative damage, and inflammatory responses as potential therapeutic strategies. Promising therapies, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and anti-inflammatory drugs, are reviewed alongside emerging approaches such as gene therapy, stem cell therapy, and immunomodulation. Despite encouraging advances, the clinical translation of these therapies remains challenging due to the complexity of DAD pathogenesis. This review aims to advance understanding of diabetes-induced cognitive impairment and guide the development of personalized dementia therapies by integrating molecular, genetic, and clinical insights. Future research should focus on elucidating the precise molecular mechanisms of DAD progression and on developing targeted, patient-specific therapeutic interventions to overcome translational barriers.

Keywords: amyloid-β; dementia; diabetes; mitochondrial dysfunction; neurodegeneration; protein aggregation and misfolding; tau.