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

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 access

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1172/jci59903

Cites

176 of 177 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

1 retracted

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

Sorted by citations

Items 801–900 of 1,005

Intestinal Flora Affect Alzheimer's Disease by Regulating Endogenous Hormones
Wu, Y., Hang, Z., Tong, L., & Du, H. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03784-w · Cited by 34
New findings on brain actions of growth hormone and potential clinical implications
Donato, J., & Kopchick, J. J. (2023) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-023-09861-x · Cited by 34
Minireview: Food for Thought: Regulation of Synaptic Function by Metabolic Hormones
McGregor, G., Malekizadeh, Y., & Harvey, J. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1328 · Cited by 34
Computational studies on Alzheimer’s disease associated pathways and regulatory patterns using microarray gene expression and network data: Revealed association with aging and other diseases
Panigrahi, P. P., & Singh, T. R. (2013) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2013.06.013 · Cited by 34
Amyloid precursor protein in pancreatic islets
Kulas, J. A., Puig, K. L., & Combs, C. K. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0122 · Cited by 34
Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice
Liu, X., Wang, W., Chen, H., Zhang, H., & Zhang, N.-X. (2019) · Acta Pharmacologica Sinica · doi:10.1038/s41401-019-0239-3 · Cited by 34
Pathogenic Feed-Forward Mechanisms in Alzheimer’s and Parkinson’s Disease Converge on GSK-3
Albeely, A. M., Ryan, S. D., & Perreault, M. L. (2018) · Brain Plasticity · doi:10.3233/bpl-180078 · Cited by 33
Combined Effect of Fatty Diet and Cognitive Decline on Brain Metabolism, Food Intake, Body Weight, and Counteraction by Intranasal Insulin Therapy in 3×Tg Mice
Sanguinetti, E., Guzzardi, M. A., Panetta, D., Tripodi, M., Sena, V. D., Quaglierini, M., Burchielli, S., Salvadori, P. A., & Iozzo, P. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00188 · Cited by 33
Loss of insulin‐like growth factor‐1 signaling in astrocytes disrupts glutamate handling
Prabhu, D., Khan, S. M., Blackburn, K., Marshall, J. P. S., & Ashpole, N. M. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14879 · Cited by 33
Plasma Clusterin as a Potential Link Between Diabetes and Alzheimer Disease
Ha, J.-H., Moon, M. K., Kim, H., Park, M., Cho, S. Y., Lee, J., Lee, J., & Kim, E. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa378 · Cited by 33
Maternal High-Fat Diet Multigenerationally Impairs Hippocampal Synaptic Plasticity and Memory in Male Rat Offspring
Lin, C., Lin, Y., Yu, J., Yu, J., Cheng, Y., Wu, X., Lin, Y., & Lin, Y. (2020) · Endocrinology · doi:10.1210/endocr/bqaa214 · Cited by 33
Pseudoginsenoside-F11 attenuates cognitive dysfunction and tau phosphorylation in sporadic Alzheimer’s disease rat model
Zhu, L., Hou, X., Che, X., Zhou, T.-S., Liu, X.-Q., Wu, C., & Yang, J. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00562-8 · Cited by 33
Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action
Zhang, J., Zhang, J., Song, J., Bai, Y., Deng, L., Feng, C., Xu, X., Guo, H.-X., Wang, Y., Gao, X., et al. (2021) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x21500658 · Cited by 33
Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier
Shin, J.-W., An, S., Kim, D., Kim, H., Ahn, J.-H., Eom, J., You, W., Yun, H., Lee, B., Sung, B., et al. (2022) · Cell Reports Methods · doi:10.1016/j.crmeth.2022.100338 · Cited by 33
Triglyceride–glucose index, Alzheimer's disease plasma biomarkers, and dementia in older adults: The MIND‐China study
Tian, N., Fa, W., Dong, Y., Liu, R., Liu, C., Liu, K., Mao, M., Zhu, M., Liang, X., Wang, N., et al. (2023) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12426 · Cited by 33
Common Signaling Pathways Involved in Alzheimer’s Disease and Stroke: Two Faces of the Same Coin
Das, T. K., Ganesh, B. P., & Fatima-Shad, K. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220108 · Cited by 33
Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal
Chung, K. M., Park, H., Jung, S., Ha, S., Yoo, S., Woo, H., Lee, H. J., Kim, S. W., Kim, E. K., Moon, C., et al. (2015) · Stem Cells · doi:10.1002/stem.2082 · Cited by 33
Metabolic actions of Rho-kinase in periphery and brain
Hu, H., Lee, D.-H., Zabolotny, J. M., & Kim, Y. (2013) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.06.003 · Cited by 33
Dysfunctional organization of default mode network before memory impairments in type 2 diabetes
Chen, Y., Liu, Z., Wang, A., Zhang, J., Zhang, S., Qi, D., Chen, K., & Zhang, Z. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.08.012 · Cited by 33
The Interaction Between Sleep and Metabolism in Alzheimer’s Disease: Cause or Consequence of Disease?
Carroll, C. M., & Macauley, S. L. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00258 · Cited by 32
Type 2 diabetes mellitus and neurodegenerative disorders: The mitochondrial connection
Baduini, I. R., Castro-Vildosola, J., Kavehmoghaddam, S., Kiliç, F., Nadeem, S. A., Nizama, J. J., Rowand, M. A., Annapureddy, D., Bryan, C.-A., Do, L. H., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107439 · Cited by 33
Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice
Wang, Z.-J., Han, W.-N., Chai, S.-F., Li, Y., Fu, C.-J., Wang, C.-F., Cai, H.-Y., Li, X., Wang, X., Hölscher, C., et al. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.11.022 · Cited by 32
A short-term, high-caloric diet has prolonged effects on brain insulin action in men
Kullmann, S., Wagner, L., Hauffe, R., Kühnel, A., Sandforth, L., Veit, R., Dannecker, C., Machann, J., Fritsche, A., Stefan, N., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01226-9 · Cited by 32
Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease
Ettcheto, M., Sánchez‐López, E., Gómez-Mínguez, Y., Cabrera, H., Busquets, O., Beas‐Zárate, C., García, M. L., Carro, E., Casadesús, G., Auladell, C., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0868-4 · Cited by 32
Midlife Insulin Resistance as a Predictor for Late-Life Cognitive Function and Cerebrovascular Lesions
Toppala, S., Ekblad, L. L., Lötjönen, J. M. P., Helin, S., Hurme, S. A. M., Johansson, J. J., Jula, A., Karrasch, M., Koikkalainen, J. R., Laine, H. K., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190691 · Cited by 32
The Role of Zinc Status on Spatial Memory, Hippocampal Synaptic Plasticity, and Insulin Signaling in icv-STZ-Induced Sporadic Alzheimer’s-Like Disease in Rats
Baltacı, S. B., Ünal, Ö., MUTLU, E. G., Gümüş, H., Pehlivanoğlu, S., Yardımcı, A., Moğulkoç, R., & Baltacı, A. K. (2021) · Biological Trace Element Research · doi:10.1007/s12011-021-02999-2 · Cited by 32
Spirulina compounds show hypoglycemic activity and intestinal flora regulation in type 2 diabetes mellitus mice
He, X., Wang, C., Zhu, Y., Jiang, X., Qiu, Y., Yin, F., Xiong, W., Liu, B., & Huang, Y. (2022) · Algal Research · doi:10.1016/j.algal.2022.102791 · Cited by 32
New animal models of Alzheimer’s disease that display insulin desensitization in the brain
Gao, C., Liu, Y., Li, L., & Hölscher, C. (2013) · Reviews in the Neurosciences · doi:10.1515/revneuro-2013-0034 · Cited by 32
The Effect of Insulin Infusion on the Metabolites in Cerebral Tissues Assessed With Proton Magnetic Resonance Spectroscopy in Young Healthy Subjects With High and Low Insulin Sensitivity
Karczewska‐Kupczewska, M., Tarasów, E., Nikołajuk, A., Stefanowicz, M., Matulewicz, N., Otziomek, E., Górska, M., Strączkowski, M., & Kowalska, I. (2013) · Diabetes Care · doi:10.2337/dc12-1437 · Cited by 32
Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level
Yang, Y., Ma, D., Xu, W., Chen, F., Du, T., Yue, W., Shao, S., & Yuan, G. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.10.005 · Cited by 32
The underexplored question of β-amyloid monomers
Copani, A. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.057 · Cited by 32
Metformin/Donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats
Obafemi, T. O., Olasehinde, O. R., Olaoye, O. A., Jaiyesimi, K. F., Adewumi, F. D., Adewale, O. B., & Afolabi, B. A. (2020) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-020-00541-0 · Cited by 32
The promise of GLP-1 receptor agonists for neurodegenerative diseases
Athauda, D. S., Greig, N. H., Meissner, W. G., Foltynie, T., & Gandhi, S. (2026) · Journal of Clinical Investigation · doi:10.1172/jci194745 · Cited by 31
Insulin resistance and carotid intima-media thickness mediate the association between resting-state heart rate variability and executive function: A path modelling study
Kemp, A. H., López, S. R., Passos, V. M. D. A., Bittencourt, M. S., Dantas, E. M., Mill, J. G., Ribeiro, A. L. P., Thayer, J. F., Benseñor, I. M., & Lotufo, P. A. (2016) · Biological Psychology · doi:10.1016/j.biopsycho.2016.04.006 · Cited by 31
RETRACTED: Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer's disease
Caccamo, A., Belfiore, R., & Oddo, S. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.03.032 · Cited by 31
Retracted
The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS1 Activation
Sposato, V., Canu, N., Fico, E., Fusco, S., Bolasco, G., Ciotti, M. T., Spinelli, M., Mercanti, D., Grassi, C., Triaca, V., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1038-4 · Cited by 31
Streptozotocin Impairs Proliferation and Differentiation of Adult Hippocampal Neural Stem Cells in Vitro-Correlation With Alterations in the Expression of Proteins Associated With the Insulin System
Sun, P., Ortega, G., Tan, Y. M., Hua, Q., Riederer, P. F., Deckert, J., & Schmitt-Böhrer, A. G. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00145 · Cited by 31
Cognitive and metabolic outcomes of vildagliptin addition to the therapy in patients with type 2 diabetes mellitus: 26 week follow-up study
Bulut, E. A., Alak, Z. Y. Ş., Dokuzlar, Ö., Koçyiğit, S. E., Soysal, P., Smith, L., & Işık, A. T. (2020) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2020.104013 · Cited by 31
Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease
Štrac, D. Š., Konjevod, M., Perković, M. N., Tudor, L., Erjavec, G. N., & Pivac, N. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200317092310 · Cited by 31
Electroacupuncture Enhances Cognition by Promoting Brain Glucose Metabolism and Inhibiting Inflammation in the APP/PS1 Mouse Model of Alzheimer’s Disease: A Pilot Study
Xu, A., Tang, Y., Zeng, Q., Wang, X., Tian, H., Zhou, Y., & Li, Z. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200242 · Cited by 31
The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice
Puig, K. L., Kulas, J. A., Franklin, W. F., Rakoczy, S. G., Taglialatela, G., Brown‐Borg, H. M., & Combs, C. K. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.12.021 · Cited by 31
Differential effects of blood insulin and HbA1c on cerebral amyloid burden and neurodegeneration in nondiabetic cognitively normal older adults
Byun, M. S., Kim, H. J., Yi, D., Choi, H. J., Baek, H., Lee, J. H., Choe, Y. M., Sohn, B. K., Lee, J., Lee, Y., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.07.004 · Cited by 31
Novel calcium-related targets of insulin in hippocampal neurons
Maimaiti, S., Frazier, H. N., Anderson, K. L., Ghoweri, A. O., Brewer, L. D., Porter, N. M., & Thibault, O. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.09.019 · Cited by 31
Partial Loss of the Glutamate Transporter GLT-1 Alters Brain Akt and Insulin Signaling in a Mouse Model of Alzheimer's Disease
Meeker, K. D., Meabon, J. S., & Cook, D. G. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-142304 · Cited by 31
Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients
Fava, A., Plastino, M., Cristiano, D., Spanò, A., Cristofaro, S., Opipari, C., Chillà, A., Casalinuovo, F., Colica, C., De Bartolo, M., et al. (2013) · Metabolic Brain Disease · doi:10.1007/s11011-013-9421-3 · Cited by 31
APOE and metabolic dysfunction in Alzheimer's disease
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.02.002 · Cited by 31
High-Fat-Diet-Induced Weight Gain Ameliorates Bone Loss without Exacerbating AβPP Processing and Cognition in Female APP/PS1 Mice
Peng, Y., Liu, J., Tang, Y., Liu, J., Han, T., Han, S., Li, H., Hou, C., Liu, J., & Long, J. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00225 · Cited by 30
Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration
Deochand, C., Tong, M., Agarwal, A., Cadenas, E., & de la Monte, S. M. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150664 · Cited by 30
Revisiting the Role of Insulin-Like Growth Factor-I Receptor Stimulating Activity and the Apolipoprotein E in Alzheimer’s Disease
Galle, S. A., van der Spek, A., Drent, M. L., Brugts, M. P., Scherder, E., Janssen, J. A. M. J. L., Ikram, M. A., & van Duijn, C. M. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00020 · Cited by 30
A Possible Neurodegeneration Mechanism Triggered by Diabetes
Farhadi, A., Vosough, M., Zhang, J., Tahamtani, Y., & Shahpasand, K. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.07.012 · Cited by 30
Metabolic syndrome exacerbates amyloid pathology in a comorbid Alzheimer's mouse model
Tyagi, A., Mirita, C., Taher, N., Shah, I., Moeller, E., Tyagi, A., Chong, T., & Pugazhenthi, S. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165849 · Cited by 30
Probiotics Fermentation Technology, a Novel Kefir Product, Ameliorates Cognitive Impairment in Streptozotocin‐Induced Sporadic Alzheimer’s Disease in Mice
Sayed, N. S. E., Kandil, E. A., & Ghoneum, M. H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5525306 · Cited by 31
Retracted
Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review
Falsetti, L., Viticchi, G., Zaccone, V., Guerrieri, E., Moroncini, G., Luzzi, S., & Silvestrini, M. (2022) · Biomedicines · doi:10.3390/biomedicines10020439 · Cited by 30
Longitudinal association between triglyceride glucose index and depression progression in middle-aged and elder adults: A national retrospective cohort study
Zheng, L., Cui, C., Yue, S., Yan, H., Zhang, T., Ding, M., Sun, Q., He, C., & Ren, H. (2022) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2022.11.015 · Cited by 30
Vascular dementia subtypes, pathophysiology, genetics, neuroimaging, biomarkers, and treatment updates along with its association with Alzheimer's dementia and diabetes mellitus
Prajjwal, P., Marsool, M. D. M., Inban, P., Sharma, B., Asharaf, S., Aleti, S., Gadam, S., Sakini, A. S. A., & Hadi, D. D. (2023) · Disease-a-Month · doi:10.1016/j.disamonth.2023.101557 · Cited by 30
Central nervous system insulin signaling can influence the rate of insulin influx into brain
Nguyễn, V. H., Thomas, P., Pemberton, S., Babin, A., Noonan, C., Weaver, R. R., Banks, W. A., & Rhea, E. M. (2023) · Fluids and Barriers of the CNS · doi:10.1186/s12987-023-00431-6 · Cited by 30
Mechanisms of action of brain insulin against neurodegenerative diseases
Ramalingam, M., & Kim, S. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-013-1147-1 · Cited by 30
Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille's heel?
Barone, E., & Butterfield, D. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.02.013 · Cited by 30
Insulin and brain aging
Baranowska-Bik, A., & Bik, W. (2017) · Menopause Review/Przegląd Menopauzalny · doi:10.5114/pm.2017.68590 · Cited by 30
Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1–40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease
Sajan, M. P., HANSEN, B. C., Higgs, M. G., Kahn, C. R., Braun, U., Leitges, M., Park, C. R., Diamond, D. M., & Farese, R. V. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.001 · Cited by 30
Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease
Burns, L. H., & Wang, H.-Y. (2017) · Neuroimmunology and Neuroinflammation · doi:10.20517/2347-8659.2017.50 · Cited by 30
Self-citation
The sodium glucose co-transporter 2 inhibitor ertugliflozin for Alzheimer's disease: Inhibition of brain insulin signaling disruption-induced tau hyperphosphorylation
Pang, B., Zhang, L., Li, B., Sun, F.-X., & Wang, Z. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114134 · Cited by 29
The Impact of Exercise Training on the Brain and Cognition in Type 2 Diabetes, and its Physiological Mediators: A Systematic Review
Vandersmissen, J., Dewachter, I., Cuypers, K., & Hansen, D. (2025) · Sports Medicine - Open · doi:10.1186/s40798-025-00836-7 · Cited by 29
Ceramides may Play a Central Role in the Pathogenesis of Alzheimer’s Disease: a Review of Evidence and Horizons for Discovery
Kalkman, H. O., & Smigielski, L. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04989-0 · Cited by 29
Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development
Xu, C., Yu, L., Hou, J., Jackson, R. J., Wang, H., Huang, C., Liu, T., Wang, Q., Zou, X., Morris, R., et al. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00330 · Cited by 29
Self-citation
Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model
Leboucher, A., Ahmed, T., Caron, É., Tailleux, A., Raison, S., Joly‐Amado, A., Marciniak, E., Carvalho, K., Hamdane, M., Bantubungi, K., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.01.008 · Cited by 29
Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis
Pacholko, A. G., Wotton, C. A., & Bekar, L. K. (2019) · Neurodegenerative Diseases · doi:10.1159/000503451 · Cited by 29
Dysfunctional proteins in neuropsychiatric disorders: From neurodegeneration to autism spectrum disorders
Jęśko, H. M., Cieślik, M., Gromadzka, G., & Adamczyk, A. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104853 · Cited by 30
Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age‐dependent manner, normalizes GABA‐activated currents in the tg‐APPSwe mouse model of Alzheimer’s disease
Hammoud, H., Netsyk, O., Tafreshiha, A. S., Korol, S. V., Jin, Z., Li, J.-P., & Birnir, B. (2021) · Acta Physiologica · doi:10.1111/apha.13623 · Cited by 29
Induction of Brain Insulin Resistance and Alzheimer’s Molecular Changes by Western Diet
Mietelska‐Porowska, A., Domańska, J. M., Want, A., Więckowska‐Gacek, A., Chutorański, D., Koperski, M., & Wojda, U. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094744 · Cited by 29
Red peppers with moderate and severe pungency prevent the memory deficit and hepatic insulin resistance in diabetic rats with Alzheimer’s disease
Yang, H. J., Kwon, D. Y., Kim, M. J., Kang, S., Moon, N. R., Daily, J. W., & Park, S. (2015) · Nutrition & Metabolism · doi:10.1186/s12986-015-0005-6 · Cited by 29
Involvement of insulin signalling pathway in methamphetamine-induced hyperphosphorylation of Tau
Xu, H., Chen, X., Wang, J., Yang, T., Liu, N., Cheng, J., Gao, R., Liu, J., & Xiao, H. (2018) · Toxicology · doi:10.1016/j.tox.2018.07.002 · Cited by 29
Cognitive impairment in patients with type 2 diabetes mellitus: prevalence, pathogenetic mechanisms, the effect of antidiabetic drugs
Ostroumova, O. D., Surkova, E. V., Chikh, E. V., Rebrova, E. V., & Borisov, M. S. (2018) · Diabetes Mellitus · doi:10.14341/dm9660 · Cited by 29
Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer’s disease and normalized by treatment with anti-diabetic agents
Katsel, P., Roussos, P., Beeri, M. S., Gama-Sosa, M. A., Gandy, S., Khan, S., & Haroutunian, V. H. (2018) · PLoS ONE · doi:10.1371/journal.pone.0206547 · Cited by 29
Altered expression of insulin‐degrading enzyme and regulator of calcineurin in the rat intracerebral streptozotocin model and human apolipoprotein E‐ε4–associated Alzheimer's disease
Delikkaya, B., Moriel, N., Tong, M., Gallucci, G. M., & de la Monte, S. M. (2019) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2019.03.004 · Cited by 29
Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice
Chan, E. S., Chen, C., Cole, G. M., & Wong, B.-S. (2015) · Scientific Reports · doi:10.1038/srep13842 · Cited by 29
Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges
Zhou, Z., Yi, L., Popławska-Domaszewicz, K., Chaudhuri, К. R., Jankovic, J. J., & Tan, E. K. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107770 · Cited by 30
When aging-onset diabetes is coming across with Alzheimer disease: Comparable pathogenesis and therapy
Tang, J., Pei, Y., & Zhou, G. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.04.013 · Cited by 28
Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases
Li, Y., Li, L., & Hölscher, C. (2016) · Reviews in the Neurosciences · doi:10.1515/revneuro-2016-0018 · Cited by 28
The Roles of Apolipoprotein E, Lipids, and Glucose in the Pathogenesis of Alzheimer’s Disease
Shinohara, M., & Sato, N. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-3540-2_5 · Cited by 28
Aβ monomer induces phosphorylation of Tau at Ser‐214 through β2AR‐PKA‐JNK signaling pathway
Wu, H., Wei, S., Huang, Y., Chen, L., Wang, Y., Wu, X., Zhang, Z., Pei, Y., & Wang, D. (2020) · The FASEB Journal · doi:10.1096/fj.201902230rr · Cited by 28
Acteoside‐improved streptozotocin‐induced learning and memory impairment by upregulating hippocampal insulin, glucose transport, and energy metabolism
Chen, J., Gao, L., Zhang, Y., Su, Y., Kong, Z., Wang, D., & Yan, M. (2020) · Phytotherapy Research · doi:10.1002/ptr.6811 · Cited by 28
Association between exenatide use and incidence of Alzheimer's disease
Zhou, B., Zissimopoulos, J., Nadeem, H., Crane, M. A., Goldman, D. P., & Romley, J. A. (2021) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12139 · Cited by 28
Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases
Butterfield, D. A., Favia, M., Spera, I., Campanella, A., Lanza, M., & Castegna, A. (2022) · Molecules · doi:10.3390/molecules27030951 · Cited by 29
Long term high fat diet induces metabolic disorders and aggravates behavioral disorders and cognitive deficits in MAPT P301L transgenic mice
Xiong, J., Deng, I. B., Kelliny, S., Lin, L., Bobrovskaya, L., & Zhou, X. (2022) · Metabolic Brain Disease · doi:10.1007/s11011-022-01029-x · Cited by 28
Ameliorative effects of bromelain on aluminum-induced Alzheimer's disease in rats through modulation of TXNIP pathway
Eraky, S. M., Ramadan, N. M., & El‐Magd, N. F. A. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.11.291 · Cited by 28
Unmasking BACE1 in aging and age-related diseases
Bao, H., & Shen, Y. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.11.008 · Cited by 28
Concordant and Discordant Cerebrospinal Fluid and Plasma Cytokine and Chemokine Responses in Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease
de la Monte, S. M., Tong, M., & Hapel, A. J. (2023) · Biomedicines · doi:10.3390/biomedicines11092394 · Cited by 28
Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid β oligomer-treated PC12 cells and primary neurons
Zhang, X., Tang, S. H., Zhang, Q.-H., Shao, W., Han, X., Wang, Y., & Du, Y. (2016) · Gene · doi:10.1016/j.gene.2016.05.018 · Cited by 28
Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease
Nagae, T., & Araki, K. (2016) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000441 · Cited by 28
Trivaric acid, a new inhibitor of PTP1b with potent beneficial effect on diabetes
Sun, W., Zhang, B., Zheng, H., Zhuang, C., Li, X., Lu, X., Quan, C., Dong, Y., Zheng, Z., & Xiu, Z. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.11.012 · Cited by 28
Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation
van der Harg, J. M., Eggels, L., Bangel, F. N., Ruigrok, S. R., Zwart, R., Hoozemans, J. J. M., la Fleur, S. E., & Scheper, W. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.04.005 · Cited by 28
Insulin Resistance Disrupts the Interaction Between AKT and the NMDA Receptor and the Inactivation of the CaMKIV/CREB Pathway in Minimal Hepatic Encephalopathy
Ding, S., Zhuge, W., Yang, J., Wen, F., Xu, Z., Wang, X., & Zhuge, Q. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx093 · Cited by 28
The role of melatonin in the onset and progression of type 3 diabetes
Song, J., Whitcomb, D. J., & Kim, B. C. (2017) · Molecular Brain · doi:10.1186/s13041-017-0315-x · Cited by 28
Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings
Duggal, P., & Mehan, S. (2019) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-190125 · Cited by 28
Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies
Shi, L., Buckley, N. J., Bos, I., Engelborghs, S., Sleegers, K., Frisoni, G. B., Wallin, A., Lleó, A., Popp, J., Martínez‐Lage, P., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.712545 · Cited by 28
The relationship between cognitive performance and insulin resistance in non‐diabetic patients with mild cognitive impairment
Kim, T., Lee, D. H., Kim, Y., Mok, J., Kim, C., Park, J., Lee, T., Yoo, K., Jeong, Y., Lee, Y., et al. (2014) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4181 · Cited by 28
Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia
Quinlan, P. S., Horváth, A., Nordlund, A., Wallin, A., & Svensson, J. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.09.018 · Cited by 27
Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology
Koren-Iton, A., Salomon‐Zimri, S., Smolar, A., Stein, E. S., Dori, A., Chapman, J., & Michaelson, D. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041289 · Cited by 28
Neuroinflammation, microglial activation, and glucose metabolism in neurodegenerative diseases
Edison, P. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.017 · Cited by 27

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks