Cognitive Dysfunction and Dementia in Type 2 Diabetes Mellitus: Insights into Mechanisms, Models, and Therapeutics

Diabetic-related cognitive dysfunction, especially mild cognitive impairment (MCI), is a serious complication of type 2 diabetes mellitus (T2DM). It severely impacts personal health and places a substantial burden on the healthcare system, characterized by deficits in cognitive function and delayed executive abilities, and accelerates dementia progression. Accurate prediction and diagnosis of MCI in T2DM patients are critical for the effective prevention and treatment of dementia. However, this task is challenging due to the diverse subtypes of MCI (amnestic and nonamnestic) and the complex underlying mechanisms. This review highlights the critical gaps in current knowledge, focusing on the unique interaction between metabolic dysregulation and neurodegenerative processes in T2DM. Emerging technologies, such as brain and vascular organoid models, have opened new avenues for unraveling these complexities, although significant challenges remain in translating these tools into clinical practice. Furthermore, we explore the neuroprotective effects of antidiabetic treatments, including sulfonylureas, biguanides, insulin, GLP-1 receptor agonists, and SGLT2 inhibitors, emphasizing their potential role in addressing the distinct mechanisms underlying different MCI subtypes. This review aims to pave the way for approaches to mitigate the burden of diabetic-related cognitive dysfunction and slow dementia progression.