Role of Insulin Resistance and Glucose Metabolism in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common disorder of the nervous system and a progressive disorder of dementia worldwide. While the amyloid-β (Aβ) plaques and neurofibrillary tangles (hyperphosphorylated tau protein) are the classical hallmarks of AD, an increasing body of evidence suggests that metabolic dysfunction, especially defects in insulin signaling, and the resulting changes in glucose metabolism are major drivers of disease pathogenesis. This review discusses recent ideas that AD is a 'type 3 diabetes' and the role of brain insulin resistance and cerebral glucose hypometabolism in neurodegeneration. Insulin signals in the CNS not only influence glucose homeostasis, but also synaptic plasticity, neurotransmission, neuronal survival, and memory formation. Dysregulation of key insulin signaling pathways such as PI3K/Akt and MAPK leads to mitochondrial dysfunction, oxidative stress, reductions in synaptic activity, and neuronal loss. The review also explores the molecular links between IR and classical AD pathologies such as amyloid-β deposition, tau hyperphosphorylation, neuroinflammation and BBB dysfunction. Genetic and lifestyle-related risk factors are also explored, including APOE ε4 genotype, obesity, high-fat diets, physical inactivity and type 2 diabetes mellitus. Further, existing and novel therapies that address metabolic dysfunction are discussed, including intranasal insulin, metformin, GLP-1 receptor agonists, PPAR-γ agonists, ketogenic therapies, and multidomain lifestyle changes (MDLC) using diet and exercise. Combining metabolic and neurodegenerative aspects offers a wider spectrum of understanding of the pathogenesis of AD and could help inform the development of new biomarkers, prevention strategies and disease-modifying treatments. The inhibition of insulin resistance and impaired glucose metabolism in the brain might therefore be a good target for early diagnosis, prevention and treatment of Alzheimer's disease.