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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Background
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Kim, W., Noh, H., Lee, Y., Jeon, J., Shanmugavadivu, A., McPhie, D. L., Kim, K., Cohen, B. M., Seo, H., & Sonntag, K. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8989-x · Cited by 56
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Tong, M., Deochand, C., Didsbury, J. R., & de la Monte, S. M. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151013 · Cited by 56
Vitamins D and E Stimulate the PI3K-AKT Signalling Pathway in Insulin-Resistant SK-N-SH Neuronal Cells
Zaulkffali, A. S., Razip, N. N. M., Alwi, S. S. S., Jalil, A. A., Mutalib, M. S. A., Gopalsamy, B., Chang, S. K., Zainal, Z., Ibrahim, N. N., Zakaria, Z. A., et al. (2019) · Nutrients · doi:10.3390/nu11102525 · Cited by 56
Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology?
Kacířová, M., Zmeškalová, A., Kořínková, L., Železná, B., Kuneš, J., & Maletı́nská, L. (2020) · Clinical Science · doi:10.1042/cs20191313 · Cited by 56
Microglial Immunometabolism in Alzheimer’s Disease
Shippy, D. C., & Ulland, T. K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.563446 · Cited by 56
Lipid metabolism in Alzheimer’s disease
Zhu, T.-B., Zhang, Z., Luo, P., Wang, S.-S., Peng, Y., Chu, S.-F., & Chen, N.-H. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.11.012 · Cited by 55
The effects of resistance exercise on cognitive function, amyloidogenesis, and neuroinflammation in Alzheimer’s disease
Azevedo, C. V., Hashiguchi, D., Campos, H. C., Figueiredo, E. V., Otaviano, S. F. S. D., Penitente, A. R., Arida, R. M., & Longo, B. M. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1131214 · Cited by 55
Mitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus
Veselov, I. M., Vinogradova, D. V., Maltsev, A. V., Shevtsov, P. N., Spirkova, E. A., Бачурин, С. О., & Shevtsova, E. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914450 · Cited by 55
Beyond amyloid: Getting real about nonamyloid targets in Alzheimer's disease
Herrup, K., Carrillo, M. C., Schenk, D., Cacace, A. M., DeSanti, S., Fremeau, R. T., Bhat, R. V., Glicksman, M. A., May, P. C., Swerdlow, R. H., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.01.017 · Cited by 55
Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease
Peineau, S., Rabiant, K., Pierrefiche, O., & Potier, B. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.018 · Cited by 56
iPSC-derived familial Alzheimer’s PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling
Moreno, C. L., Guardia, L. D., Shnyder, V., Ortiz‐Virumbrales, M., Kruglikov, I., Zhang, B., Schadt, E. E., Tanzi, R. E., Noggle, S., Buettner, C., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0265-5 · Cited by 55
Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model
Imamura, T., Yanagihara, Y. T., Ohyagi, Y., Nakamura, N., Iinuma, K., Yamasaki, R., Asai, H., Maeda, M., Murakami, K., Irie, K., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104739 · Cited by 55
The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD
Cheng, L., Liu, W., Li, X., Zhang, Z., Qi, H., Liu, S., Yan, N., Xing, Y., Hölscher, C., & Wang, Z. (2020) · Brain and Behavior · doi:10.1002/brb3.1505 · Cited by 55
Insulin growth factor binding protein 7 is a novel target to treat dementia
Agbemenyah, H. Y., Agís‐Balboa, R. C., Burkhardt, S., Delalle, I., & Fischer, A. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.09.011 · Cited by 55
Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging
Thambisetty, M., Beason-Held, L. L., An, Y., Kraut, M., Metter, J., Egan, J., Ferrucci, L., O'Brien, R., & Resnick, S. M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.03.025 · Cited by 54
Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer’s disease models: a systematic review and meta-analysis of preclinical studies
Kong, F., Wu, T., Dai, J., Zhai, Z., Cai, J., Zhu, Z., Xu, Y., & Sun, T. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1205207 · Cited by 54
Cognitive Enhancing Treatment with a PPARγ Agonist Normalizes Dentate Granule Cell Presynaptic Function in Tg2576 APP Mice
Nenov, M. N., Laezza, F., Haidacher, S. J., Zhao, Y., Sadygov, R. G., Starkey, J. M., Spratt, H. M., Luxon, B. A., Dineley, K. T., & Denner, L. A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3413-13.2014 · Cited by 54
Unraveling Alzheimer’s: Making Sense of the Relationship between Diabetes and Alzheimer’s Disease
Schilling, M. A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150980 · Cited by 54
Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice
Wang, P., Su, C., Feng, H., Chen, X., Dong, Y., Rao, Y., Ren, Y., Yang, J.-D., Shi, J., Tian, J., et al. (2017) · International Journal of Immunopathology and Pharmacology · doi:10.1177/0394632016688025 · Cited by 54
Physical exercise protocols in animal models of Alzheimer’s disease: a systematic review
Sousa, R. A. L. D., Rodrigues, C. M., Mendes, B. F., Caria, A. C. I., Dias‐Peixoto, M. F., & Cassilhas, R. C. (2020) · Metabolic Brain Disease · doi:10.1007/s11011-020-00633-z · Cited by 54
Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease
Cummings, J. L., Ortiz, A. A., Castellino, J., & Kinney, J. W. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15619 · Cited by 54
Perspectives in Lipocalin-2: Emerging Biomarker for Medical Diagnosis and Prognosis for Alzheimer's Disease
Song, J., & Kim, O. Y. (2018) · Clinical Nutrition Research · doi:10.7762/cnr.2018.7.1.1 · Cited by 53
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Silzer, T. K., & Phillips, N. R. (2018) · Mitochondrion · doi:10.1016/j.mito.2018.04.004 · Cited by 53
Brain insulin resistance and cognitive function: influence of exercise
Malin, S. K., Stewart, N. R., Ude, A. A., & Alderman, B. L. (2022) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00375.2022 · Cited by 53
A Network-Based Classification Model for Deriving Novel Drug-Disease Associations and Assessing Their Molecular Actions
Oh, M., Ahn, J., & Yoon, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111668 · Cited by 53
Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease
Triani, F., Tramutola, A., Domenico, F. D., Sharma, N. K., Butterfield, D. A., Head, E., Marzia Perluigi, A., & Barone, E. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.005 · Cited by 53
The “great” controlling nucleotide coenzymes
Veech, R. L., King, M. T., Pawlosky, R. J., Kashiwaya, Y., Bradshaw, P. C., & Curtis, W. (2019) · IUBMB Life · doi:10.1002/iub.1997 · Cited by 53
Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer's disease
Sharma, V., & Singh, T. G. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118401 · Cited by 52
Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons
Giuffrida, M. L., Tomasello, M. F., Pandini, G., Caraci, F., Battaglia, G., Busceti, C., Di Pietro, P., Pappalardo, G., Attanasio, F., Chiechio, S., et al. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00297 · Cited by 52
Maternal Cognitive Impairment Associated with Gestational Diabetes Mellitus—A Review of Potential Contributing Mechanisms
John, C. M., Yusof, N. I. S. M., Aziz, S. H. A., & Fauzi, F. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123894 · Cited by 52
Type 3 Diabetes Mellitus: A Link Between Alzheimer's Disease and Type 2 Diabetes Mellitus
Nisar, O., Pervez, H., Mandalia, B., Waqas, M., & Sra, H. K. (2020) · Cureus · doi:10.7759/cureus.11703 · Cited by 52

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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