A systematic review on type 3 diabetes: bridging the gap between metabolic dysfunction and Alzheimer’s disease

Alzheimer's disease (AD) is increasingly associated with metabolic dysfunction, particularly insulin resistance, which impairs neuronal signaling and energy metabolism. Disruption of brain insulin pathways contributes to amyloid-beta accumulation, tau pathology, and neuroinflammation. These shared features have led to the concept of "Type 3 Diabetes" (T3D). This review aims to investigate the molecular links between insulin resistance and AD and to highlight emerging therapeutic strategies. A systematic review was conducted in accordance with PRISMA guidelines using PubMed, Scopus, Web of Science, and the Cochrane Library to identify studies published between January 2010 and July 2025. Search terms included "Diabetes Mellitus", "Insulin Resistance", "Alzheimer Disease", "Nerve Degeneration", "Cognitive Dysfunction", and other related molecular and clinical keywords. After removing duplicates and applying predefined inclusion and exclusion criteria, a total of 213 peer-reviewed articles were included in the final analysis. Insulin resistance was consistently identified as a key pathological driver, impairing brain glucose uptake, amyloid-beta clearance, and tau phosphorylation. Disruption of insulin signaling pathways, especially PI3K/Akt and GLUT4 translocation, was associated with neuroinflammation, oxidative stress, and cognitive decline. Additionally, transcriptomic data highlighted the role of non-coding RNAs, including MEG3 and MALAT1, in modulating insulin sensitivity and glucose homeostasis, linking metabolic imbalance to neuronal dysfunction. Insulin resistance and disrupted glucose metabolism play a central role in the development and progression of AD, supporting the concept of T3D. Targeting these pathways shows promising neuroprotective potential. Future studies should focus on validating these interventions in large-scale clinical trials.