Diabetes-Associated Cognitive Dysfunction: Pathophysiology, Molecular Mechanisms, and Emerging Therapeutic Strategies

Diabetes-associated cognitive dysfunction (DACD), which includes memory loss, executive dysfunction, attention, processing speed, and an increased risk of dementia, is a growing problem associated with diabetes mellitus (DM), especially type 2 diabetes mellitus. Due to a significant increase in the global burden of diabetes and population ageing, DACD is becoming an important public health issue. This review provides a comprehensive overview of the pathophysiology, molecular mechanisms, biomarkers, experimental models, and emerging therapeutic strategies associated with DACD. At present, it is believed that the multiple mechanisms associated with chronic hyperglycemia, insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, blood-brain barrier disruption, and microvascular injury all contribute to the pathogenesis of DACD. These interrelated mechanisms are responsible for cognitive decline, synaptic dysfunction, and neuronal damage. Experimental research has shown that specific molecular pathways contribute to the pathogenesis of DACD, such as AGE-RAGE signaling, nuclear factor-κB activation, PI3K/Akt dysregulation, and inflammatory cascades. Emerging biomarkers including neurofilament light (NfL) chain, phosphorylated tau (p-tau), neuroimaging markers, exosomes, metabolomic profiles, and transcriptomic signatures may improve early diagnosis and risk stratification. Several therapeutic approaches, including GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, intranasal insulin, nanoparticle-based delivery systems, stem cell therapies, and bioactive compounds, have demonstrated promising neuroprotective effects in preclinical studies, although clinical translation remains limited. Finally, future studies should be directed toward the use of biomarker-driven diagnosis, clinically relevant disease models, and large-scale clinical studies in order to develop effective therapeutic interventions. Understanding more of the mechanisms that underlie DACD could help inform the creation of precision medicine strategies to prevent or delay diabetes-related cognitive decline.