Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches
Open accessAbstract
Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid β peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.
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Insulin resistance affects the clearance of amyloid-β, the hyperphosphorylation of tau, and glucose metabolism, and enhances the aberrant expression of α-synuclein.
“In addition, insulin resistance affects the clearance of Aβ, the hyperphosphorylation of tau, and glucose metabolism and enhances the aberrant expression of α-syn.356,357”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [356]
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“334,335 The PI3K-Akt pathway is a crucial component of insulin signaling, and in AD brains, there is observed a decrease in IRS-associated PI3K activity and reduced phosphorylation of Akt kinase.”
BackgroundMitochondrial dysfunction in neurodegenerative disorders
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- Authors
- Kellar, D., & Craft, S.
- Affiliations
- Wake Forest University Health Sciences (US)
- Corresponding author
- Craft, Suzanne
- ORCID
- Craft, Suzanne
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 19
- Issue
- 9
- Pages
- 758-766
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC9661919
- OpenAlex
- W3045828365
- Cited by
- 832
- References
- 104
- Citations by year
- 2026: 132 · 2025: 157 · 2024: 150 · 2023: 154 · 2022: 142 · 2021: 87 · 2020: 10
- FWCI
- 12.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30AG049638, P30AG072947)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- brain insulin resistance, Alzheimer's disease, insulin signaling, synaptic function, dendritic spine formation, dopamine turnover, proteostasis, amyloid-beta clearance, tau phosphorylation, neuroinflammation, vascular function, lipid metabolism, vascular cognitive impairment, neurodegeneration, treatment options
- MeSH terms
- Glucagon-Like Peptide-1 Receptor Agonists, Alzheimer Disease, Animals, Brain, Humans, Insulin, Insulin Resistance, Risk Reduction Behavior
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