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

Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) share overlapping pathophysiological pathways, including metabolic reprogramming, oxidative stress, and impaired cellular homeostasis.

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.

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.

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.