Research Progress on Pathology, Molecular Mechanisms, and Intervention Strategies of Cognitive Dysfunction Associated with Type 2 Diabetes

Abstract: Type 2 diabetes–associated cognitive dysfunction (DACD) is a major neurological complication of type 2 diabetes mellitus (T2DM). Against the backdrop of global population aging and the rising prevalence of T2DM, DACD poses a substantial challenge to public health. The pathogenesis of DACD involves the interplay of multiple signaling pathways and pathological processes, which remain incompletely understood. This review aims to systematically delineate the interconnections and regulatory networks among core mechanisms in DACD, including glucose transporter dysfunction, the oxidative stress–mitochondrial dysfunction–neuroinflammation axis, ferroptosis, the microbiota–gut–brain axis, autophagy, and epigenetic modifications. By integrating recent research advances in these mechanisms, this review provides a comprehensive understanding of the pathology of DACD and proposes multi-target intervention strategies from an integrated perspective, thereby offering insights for the development of future therapeutic approaches. This integrated framework is expected to provide new theoretical perspectives for clinicians and translational medicine researchers, to promote the development of diagnostic tools integrating multi-omics biomarkers, and to offer references for optimizing combination treatment strategies targeting key nodes across multiple mechanisms. The primary limitation of this review is that the conclusions are based predominantly on preclinical evidence; future clinical translation will require further validation through large-scale studies. Plain Language Summary: A growing number of patients with type 2 diabetes experience declines in cognitive abilities and memory—a condition known as diabetes-associated cognitive dysfunction (DACD). This disorder imposes a substantial burden on families and society. Researchers have found that DACD is not caused by a single factor but rather by multiple interconnected brain abnormalities that influence each other like a network. This review aims to elucidate these complex mechanisms—including oxidative stress, mitochondrial dysfunction, neuroinflammation, ferroptosis, gut microbiota–brain communication, autophagy, and epigenetic regulation—and explain how they interact to ultimately impair cognitive function. Importantly, we summarize various potential treatment strategies based on these new findings, including pharmacological agents, natural metabolites, and non-pharmacological therapies. By providing this integrated perspective, we hope to guide the development of more effective preventive and therapeutic strategies in the future, ultimately improving the quality of life for individuals with diabetes. Keywords: type 2 diabetes, cognitive dysfunction, oxidative stress, ferroptosis, microbiota–gut–brain axis, neuroinflammation