Cited by 1,871Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

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Talbot, Konrad, Wang, Hoau-Yan, Kazi, Hala, Han, Li-Ying, Bakshi, Kalindi P., Stucky, Andres, Fuino, Robert L., Kawaguchi, Krista R., Samoyedny, Andrew J., Wilson, Robert S., Arvanitakis, Zoe, Schneider, Julie A., Wolf, Bryan A., Bennett, David A., Trojanowski, John Q., Arnold, Steven E.·2012·Journal of Clinical Investigation

DOI 10.1172/jci59903PMC PMC3314463

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Abstract

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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RETRACTED: Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone
Pratchayasakul, W., Kerdphoo, S., Petsophonsakul, P., Pongchaidecha, A., Chattipakorn, N., & Chattipakorn, S. C. (2011) · Life Sciences · doi:10.1016/j.lfs.2011.02.003 · Cited by 206
Retracted
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 4×
“The other was the hippocampal formation (HF; consisting of hippocampus fields CA1–CA3, the dentate gyrus, and the subiculum), which develops marked pathology starting early in the disorder (61, 63).”
BackgroundInfluential
Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155
Self-citation
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685
Phases of Aβ-deposition in the human brain and its relevance for the development of AD
Thal, D. R., Rüb, U., Orantes, M., & Braak, H. (2002) · Neurology · doi:10.1212/wnl.58.12.1791 · Cited by 3,490
Critical nodes in signalling pathways: insights into insulin action
Taniguchi, C. M., Emanuelli, B., & Kahn, C. R. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1837 · Cited by 2,760
A comprehensive definition for metabolic syndrome
Huang, P. L. (2009) · Disease Models & Mechanisms · doi:10.1242/dmm.001180 · Cited by 2,223
Risk of dementia in diabetes mellitus: a systematic review
Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., & Scheltens, P. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70284-2 · Cited by 2,187
Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system.
de Nó, R. L. (1934) · Cited by 1,974

Flagged first, then by citations

Show all 176 references

Research works printed but not linked: 5

Cheatham, 1995, Endocr Rev., 16, 117
Combettes-Souverain, 1998, Diabetes Metab., 24, 477
10.1210/en.143.1.276 · DOI
García-Lara, 2010, Rev Invest Clin., 62, 343
Lorente de Nò, 1934, J Psychol Neurol., 46, 113

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Stoeckel, L. E., Arvanitakis, Z., Gandy, S., Small, D. M., Kahn, C. R., Pascual‐Leone, Á., Pawlyk, A. C., Sherwin, R., & Smith, P. (2016) · F1000Research · doi:10.12688/f1000research.8300.2 · Cited by 113
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Mao, Y., Guo, Z., Zheng, T., Jiang, Y., Yan, Y., Yin, X., Chen, Y., & Zhang, B. (2016) · Aging Cell · doi:10.1111/acel.12498 · Cited by 113
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Lavin, D. P., White, M. F., & Brazil, D. P. (2016) · Diabetologia · doi:10.1007/s00125-016-4072-7 · Cited by 113
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Cerebrovascular insulin receptors are defective in Alzheimer’s disease
Leclerc, M., Bourassa, P., Tremblay, C., Caron, V., Sugère, C., Émond, V., Bennett, D. A., & Calon, F. (2022) · Brain · doi:10.1093/brain/awac309 · Cited by 113
Self-citation
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Rae, C. D., Baur, J. A., Borges, K., Dienel, G. A., Díaz‐García, C. M., Douglass, S. R., Drew, K. L., Duarte, J. M. N., Durán, J., Kann, O., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16032 · Cited by 113
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Chen, Y., Zhao, S., Fan, Z., Li, Z., Zhu, Y., Shen, T., Li, K., Yan, Y., Tian, J., Liu, Z., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00761-9 · Cited by 111
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Chapman, C. D., Schiöth, H. B., Grillo, C. A., & Benedict, C. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.037 · Cited by 111
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Shieh, J. C.-C., Huang, P.-T., & Lin, Y. (2020) · Molecular Neurobiology · doi:10.1007/s12035-019-01858-5 · Cited by 111
Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention
Peng, Y., Gao, P., Shi, L., Chen, L., Liu, J., & Long, J. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7763 · Cited by 110
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Blázquez, E., Hurtado-Carneiro, V., Ayuso, Y. L. B., Velázquez, E., García‐García, L., Gómez-Oliver, F., Ruiz‐Albusac, J. M., Ávila, J., & Pozo, M. A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.873301 · Cited by 110
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Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review
Rao, R. V., Subramaniam, K. G., Gregory, J., Bredesen, A. L., Coward, C., Okada, S., Kelly, L., & Bredesen, D. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021659 · Cited by 109
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Pan, R.-Y., Zhang, J., Wang, J., Wang, Y., Li, Z., Liao, Y., Liao, Y., Zhang, C., Liu, Z., Song, L., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00311-y · Cited by 107
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Duarte, J. M. N. (2014) · Aging and Disease · doi:10.14336/ad.2014.1104 · Cited by 107
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Reinhardt, S., Schuck, F., Grösgen, S., Riemenschneider, M. J., Hartmann, T., Postina, R., Grimm, M. O. W., & Endres, K. (2013) · The FASEB Journal · doi:10.1096/fj.13-234864 · Cited by 107
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Pellegrino, A., Coppola, G., Santopaolo, F., Gasbarrini, A., & Ponziani, F. R. (2023) · Nutrients · doi:10.3390/nu15081815 · Cited by 107
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Vandal, M., White, P. J., Chevrier, G., Tremblay, C., St‐Amour, I., Planel, E., Marette, A., & Calon, F. (2015) · The FASEB Journal · doi:10.1096/fj.14-268482 · Cited by 107
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Ruiz, H. H., Chi, T., Shin, A. C., Lindtner, C., Hsieh, W., Ehrlich, M. E., Gandy, S., & Buettner, C. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.01.008 · Cited by 107
Slow Excitotoxicity in Alzheimer's Disease
Ong, W.-Y., Tanaka, K., Dawe, G. S., Ittner, L. M., & Farooqui, A. A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121990 · Cited by 106

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: Talbot, Konrad
Wang, Hoau-Yan
Arvanitakis, Zoe
Schneider, Julie A.
Bennett, David A.
Trojanowski, John Q.
Arnold, Steven E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2012-04-02
Volume: 122
Issue: 4
Pages: 1316-1338
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci59903
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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Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

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