The DOI matches its Crossref record; 176 of the 177 references it cites were found in a registry or an index, and 1 are not checked yet.
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 a disruption in insulin/IGF1 signalling mediated via AKT in cultured neurons, and these mice show impaired memory37.”
From A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease (2018) · cites this paper as [37]
In the citing paper
“Further, administration of an INPPL1 inhibitor to a mouse model of diabetes was able to rescue the synaptic plasticity and memory defects observed in this model.”
From A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease (2018) · cites this paper as [37]
In the citing paper
“and the AD brain displays insulin resistance and impaired mitochondrial function (45,46)”
From Altered mitochondrial function in insulin-deficient and insulin-resistant states (2018) · cites this paper as [45]
In the citing paper
“insulin signalling cascades in post-mortem hippocampal tissue from elderly individuals with or without AD 132 (all of them 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.”
From Intranasal insulin (2021) · cites this paper as [132]
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A Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer’s Disease
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Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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