Tahereh Jamshidnejad-tosaramandani

Title: Insulin metabolism role in Alzheimer’s disease

Abstract

Alterations in insulin metabolism have become increasingly recognized as central contributors to the pathophysiology of Alzheimer’s disease (AD). Beyond its classical role in glucose regulation, insulin acts as a neuromodulator within the brain, influencing synaptic plasticity, neuronal survival, learning, and memory. Impaired insulin signaling, often described as “brain insulin resistance”, has been linked to hallmark AD processes, including amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, and chronic neuroinflammation. This presentation examines the mechanistic relationship between disrupted insulin pathways and neurodegeneration in AD.

Insulin receptors are widely expressed in hippocampal and cortical regions, where proper signaling supports long-term potentiation and neurotransmitter balance. In AD insulin resistance promotes Aβ generation by altering APP processing, while diminished insulin-degrading enzyme activity reduces Aβ clearance. Concurrently, dysregulated insulin signaling enhances tau pathology through increased GSK-3β–mediated phosphorylation.

Peripheral metabolic disturbances, including type 2 diabetes, obesity, and hyperinsulinemia, further exacerbate central insulin resistance and elevate AD risk. Emerging evidence suggests that restoring insulin sensitivity, either through lifestyle interventions or pharmacological agents, may attenuate disease progression. Intranasal insulin delivery has shown potential in improving cognitive performance by directly targeting central insulin pathways without systemic side effects.

Understanding the interplay between insulin metabolism and AD provides a foundation for developing metabolic-centered therapeutic strategies. Clarifying these mechanisms may advance early diagnosis, guide personalized treatment approaches, and support ongoing efforts to redefine AD as a neuro-metabolic disorder.

Audience Takeaway from Presentation:

1. Brain insulin resistance is a core driver of Alzheimer’s pathology, contributing directly to amyloid-β accumulation, tau hyperphosphorylation, and synaptic dysfunction.

2. Metabolic disorders such as type 2 diabetes and hyperinsulinemia significantly increase Alzheimer’s risk by worsening central insulin signaling and promoting neuroinflammation.

3. Targeting insulin pathways, including intranasal insulin delivery and insulin-sensitizing therapies, represents a promising therapeutic direction for slowing cognitive decline and modifying disease progression.