Interaction of insulin hormone with neurotransmitters in the pathogenesis of Alzheimer's disease
TL;DR
Cerebral insulin resistance is an important and targetable causal component in the pathogenesis of AD and targeting this pathway is a promising therapeutic strategy, however, challenges such as standardization of measurement, rigorous trial design, and crossing the blood-brain barrier require attention before widespread clinical application.
Abstract
Background : The association between insulin resistance and Alzheimer's disease (AD) has been proposed as the "type 3 diabetes" hypothesis. This systematic review investigates the role of impaired cerebral insulin signaling in the pathogenesis of AD and its therapeutic prospects. Materials and methods : Following the PRISMA guidelines, a comprehensive search was conducted in PubMed/MEDLINE, Scopus, and Web of Science databases up to 2025. After screening, 32 studies were included in the review. Results : Cerebral insulin resistance is a key pathological factor in AD that acts through independent mechanisms. It impairs amyloid-beta (Aβ) clearance by reducing the activity of insulin-degrading enzyme (IDE) and by disrupting the PI3K/Akt pathway, leads to GSK-3β activation and tau hyperphosphorylation. These processes, together with impaired neurotransmission and inflammation, form a vicious cycle of neurodegeneration and support the concept of type 3 diabetes. In contrast, emerging therapies such as intranasal insulin and GLP-1 agonists have shown potential to improve molecular markers and cognition in early studies. Conclusion : Cerebral insulin resistance is an important and targetable causal component in the pathogenesis of AD. Targeting this pathway is a promising therapeutic strategy. However, challenges such as standardization of measurement, rigorous trial design, and crossing the blood-brain barrier require attention before widespread clinical application. Future research should focus on identifying biomarkers and developing combination therapies.