Researchers have considered a role for dysregulation of insulin metabolism in the development of Alzheimer’s disease, to the point of suggesting that it might be classified as a type 3 diabetes. Epidemiological data shows that Alzheimer’s is nowhere near as clearly a direct, reliable consequence of obesity and consequent metabolic dysfunction as is the case for type 2 diabetes, however, indicating that the story is probably more complex. Here, researchers discuss the role of insulin resistance in Alzheimer’s disease and the existing body of evidence, pro and con, relating to approaches to therapy based on insulin delivery.
The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging.
Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagonlike peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative stress and neuroinflammation.
This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative stress regulation, as these are pivotal in both Alzheimer’s disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.