Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
Open accessAbstract
While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.
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Transgenic mice overexpressing INPPL1 show disruption in insulin/IGF1 signalling via AKT in cultured neurons, and these mice show impaired memory.
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In an ex vivo stimulation study, insulin signalling cascades in post-mortem hippocampal tissue from elderly individuals with or without AD (all without a history of diabetes) were strongly impaired in AD patients compared to controls matched for age and sex, and these impairments were negatively related to scores of cognition and memory.
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- Authors
- Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., Fuino, R. L., Kawaguchi, K. R., Samoyedny, A. J., Wilson, R. S., Arvanitakis, Z., Schneider, J. A., Wolf, B. A., Bennett, D. A., Trojanowski, J. Q., & Arnold, S. E.
- Affiliations
- University of Pennsylvania (US)
- City University of New York (US)
- Rush University Medical Center (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Talbot, Konrad
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-04-02
- Volume
- 122
- Issue
- 4
- Pages
- 1316-1338
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3314463
- OpenAlex
- W1982795519
- Cited by
- 1,871
- References
- 176
- Citations by year
- 2026: 118 · 2025: 147 · 2024: 120 · 2023: 114 · 2022: 157 · 2021: 168 · 2020: 175 · 2019: 145 · 2018: 146 · 2017: 109 · 2016: 116 · 2015: 125 · 2014: 111 · 2013: 93 · 2012: 26
- FWCI
- 75.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (P30AG10161, R01 AG15819)
- University of Pennsylvania
- Rush University (R01 AG15819)
- T.L.L Temple Foundation
- National Institute on Aging (P30AG010124, R01AG015819, AG-10124, P30AG010161)
- National Institute of General Medical Sciences (R25GM056833)
- 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
- Alzheimer's disease, brain insulin resistance, IGF-1 resistance, IRS-1, IRS-1 serine phosphorylation, insulin signaling, PI3K signaling, IGF-1 receptor, hippocampus, cerebellum, amyloid-beta oligomers, cognitive decline, episodic memory, working memory, APOE ε4, neurofibrillary tangles, mild cognitive impairment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebellar Cortex, Cognition Disorders, Drug Resistance, Female, Glucose, Hippocampus, Humans, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Male, Middle Aged, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Recombinant Proteins, Signal Transduction, Diabetes Complications, Apolipoprotein E4, Insulin Receptor Substrate Proteins
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