Insulin resistance and cognitive decline: the metabolic mechanisms linking type 2 diabetes to Alzheimer's disease.

Abstract

<h4>Background</h4>Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) share overlapping pathophysiological pathways, including metabolic reprogramming, oxidative stress, and impaired cellular homeostasis.<h4>Methods</h4>This review explored the role of metabolism in mediating these processes and its implications for neurodegeneration and metabolic dysfunction in T2DM and AD. A detailed analysis of the current literature was performed using MESH terms on relevant databases (Google Scholar, PubMed, Embase, and Cochrane Library) to systematically observe the causes of cognitive impairment.<h4>Results</h4>Overexpression of Branched Chain Amino Acid (BCAA) is linked to significant disruptions in glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, leading to reduced acetyl-CoA availability and increased production of reactive oxygen species (ROS). These metabolic disturbances contribute to dysregulated autophagy and the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. High glucose levels, characteristic of T2DM, exacerbate Branched Chain Amino T 1-associated dysregulation, amplifying neuronal death and oxidative damage. Interestingly, BCAA supplementation helps counteract certain negative effects by boosting ATP production, indicating a dual role in the progression of the disease. Additionally, the interactions with redox-sensitive enzymes and autophagy pathways further provide evidence of its role in regulating cellular homeostasis.<h4>Conclusion</h4>These findings provide a base for researchers for further research on metabolic pathway modulation, advanced biomarker discovery, precision medicine, targeted antioxidant therapies, and AI-driven predictive modelling. Novel BCAA modulators offer a promising therapeutic direction, potentially bridging the gap between metabolic and neurodegenerative disorders, providing a foundation for innovative interventions in cognitive impairment.