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 101–200 of 1,005

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel
Kunkle, B. W., Schmidt, M. A., Klein, H., Naj, A. C., Hamilton‐Nelson, K. L., Larson, E. B., Evans, D. A., Jager, P. L. D., Crane, P. K., Buxbaum, J. D., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.3536 · Cited by 258
Self-citation
Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior
Soto, M., Cai, W., Konishi, M., & Kahn, C. R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817391116 · Cited by 253
Systemic and central nervous system metabolic alterations in Alzheimer’s disease
van der Velpen, V., Teav, T., Gallart‐Ayala, H., Mehl, F., Konz, I., Clark, C., Oikonomidi, A., Peyratout, G., Henry, H., Delorenzi, M., et al. (2019) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0551-7 · Cited by 254
The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease
Batista, A. F., Forny‐Germano, L., Clarke, J. R., Silva, N. M. L. E., Brito‐Moreira, J., Boehnke, S. E., Winterborn, A., Coe, B. C., Lablans, A., Vital, J. F. S., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5056 · Cited by 251
High-Fat Diet Induces Hepatic Insulin Resistance and Impairment of Synaptic Plasticity
Liu, Z., Patil, I., Jiang, T., Sancheti, H., Walsh, J. P., Stiles, B. L., Yin, F., & Cadenas, E. (2015) · PLoS ONE · doi:10.1371/journal.pone.0128274 · Cited by 250
The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review
Reich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248
Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism
Ferris, H. A., Perry, R. J., Moreira, G. V., Shulman, G. I., Horton, J. D., & Kahn, C. R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620506114 · Cited by 246
The Role of Ketogenic Diet in the Treatment of Neurological Diseases
Dyńka, D., Kowalcze, K., & Paziewska, A. (2022) · Nutrients · doi:10.3390/nu14235003 · Cited by 245
Insulin Reverses the High-Fat Diet–Induced Increase in Brain Aβ and Improves Memory in an Animal Model of Alzheimer Disease
Vandal, M., White, P. J., Tremblay, C., St‐Amour, I., Chevrier, G., Émond, V., Lefrançois, D., Virgili, J., Planel, E., Giguère, Y., et al. (2014) · Diabetes · doi:10.2337/db14-0375 · Cited by 243
Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches
Hussain, R., Zubair, H., Sarah, P., & Shahab, M. (2018) · Brain Sciences · doi:10.3390/brainsci8090177 · Cited by 244
Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress
Dewanjee, S., Chakraborty, P., Bhattacharya, H., Chacko, L., Singh, B., Chaudhary, A., Javvaji, K., Pradhan, S. R., Vallamkondu, J., Dey, A., et al. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.09.032 · Cited by 243
Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease
Burillo, J., Marqués, P., Jiménez, B., González-Blanco, C., Benito, M., & Guillén, C. (2021) · Cells · doi:10.3390/cells10051236 · Cited by 246
Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging
Kapogiannis, D., Mustapic, M., Shardell, M. D., Berkowitz, S. T., Diehl, T. C., Spangler, R. D., Tran, J., Lazaropoulos, M. P., Chawla, S., Gulyani, S., et al. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.2462 · Cited by 241
Insulin, cognition, and dementia
Cholerton, B., Baker, L. D., & Craft, S. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.08.008 · Cited by 243
Insulin Resistance in Alzheimer's Disease
Ferreira, L. S. S., Fernandes, C., Vieira, M. N. N., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00830 · Cited by 238
Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus
Ashraf, G., Greig, N., Khan, T., Hassan, I., Tabrez, S., Shakil, S., Sheikh, I., Zaidi, S., Akram, M., Jabir, N., et al. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666140917095514 · Cited by 236
The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia
Yang, L., Wang, H., Liu, L., & Xie, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00073 · Cited by 236
Self-citation
Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease
Yarchoan, M. M., & Arnold, S. E. (2014) · Diabetes · doi:10.2337/db14-0287 · Cited by 234
Self-citation
Review: Astrocytes in Alzheimer's disease and other age‐associated dementias: a supporting player with a central role
Garwood, C. J., Ratcliffe, L. E., Simpson, J. E., Heath, P. R., Ince, P. G., & Wharton, S. B. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12338 · Cited by 233
Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology
Abner, E. L., Nelson, P. T., Kryscio, R. J., Schmitt, F. A., Fardo, D. W., Woltjer, R. L., Cairns, N. J., Yu, L., Dodge, H. H., Xiong, C., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.12.006 · Cited by 233
Self-citation
Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes
Bai, L., Gao, J., Wei, F., Zhao, J., Wang, D., & Wei, J. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00423 · Cited by 233
Obesity as a risk factor for Alzheimer's disease: weighing the evidence
Alford, S., Patel, D. K., Perakakis, N., & Mantzoros, C. S. (2017) · Obesity Reviews · doi:10.1111/obr.12629 · Cited by 232
Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases
Meredith, M. E., Salameh, T. S., & Banks, W. A. (2015) · The AAPS Journal · doi:10.1208/s12248-015-9719-7 · Cited by 231
Insulin regulates astrocyte gliotransmission and modulates behavior
Cai, W., Xue, C., Sakaguchi, M., Konishi, M., Shirazian, A., Ferris, H. A., Li, M. E., Yu, R., Kleinridders, A., Pothos, E. N., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99366 · Cited by 229
Mitochondrial dysfunction in Alzheimer’s disease
D’Alessandro, M. C. B., Kanaan, S., Geller, M., Praticò, D., & Daher, J. P. L. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102713 · Cited by 240
Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease
Mullins, R. J., Diehl, T. C., Chia, C. W., & Kapogiannis, D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00118 · Cited by 227
Atypical, non-standard functions of the microtubule associated Tau protein
Sotiropoulos, I., Galas, M., Silva, J. M., Skoulakis, E. M. C., Wegmann, S., Maina, M. B., Blum, D. L., Sayas, C. L., Mandelkow, E., Mandelkow�, E., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0489-6 · Cited by 221
Insulin action at a molecular level – 100 years of progress
White, M. F., & Kahn, C. R. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101304 · Cited by 221
Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study)
Femminella, G. D., Frangou, E., Love, S., Busza, G., Holmes, C., Ritchie, C. W., Lawrence, R., McFarlane, B., Tadros, G., Ridha, B. H., et al. (2019) · Trials · doi:10.1186/s13063-019-3259-x · Cited by 220
Is Alzheimer’s disease a systemic disease?
Morris, J. K., Honea, R. A., Vidoni, E. D., Swerdlow, R. H., & Burns, J. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.012 · Cited by 219
Alzheimer's therapeutics: Continued clinical failures question the validity of the amyloid hypothesis—but what lies beyond?
Mullane, K., & Williams, M. J. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.11.014 · Cited by 219
The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction
Zilberter, Y., & Zilberter, M. Y. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24064 · Cited by 222
Triglycerides cross the blood–brain barrier and induce central leptin and insulin receptor resistance
Banks, W. A., Farr, S. A., Salameh, T. S., Niehoff, M. L., Rhea, E. M., Morley, J. E., Hanson, A. J., Hansen, K. M., & Craft, S. (2017) · International Journal of Obesity · doi:10.1038/ijo.2017.231 · Cited by 216
Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies
Yarchoan, M. M., Toledo, J. B., Lee, E. B., Arvanitakis, Z., Kazi, H., Han, L.-Y., Louneva, N., Lee, V. M. ‐., Kim, S. F., Trojanowski, J. Q., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1328-5 · Cited by 215
Self-citation
Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment
Анатольевич, П. И., Costa-Nunes, J. P., Kasatkin, V. N., Veniaminova, E. A., Demchenko, A. G., Lyundup, A. V., Lesch, K., Ponomarev, E. D., & Strekalova, T. V. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12866 · Cited by 215
Metabolic Inflammation—A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?
Gehrke, N., & Schattenberg, J. M. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.02.020 · Cited by 216
Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation
Clarke, J. R., Lyra e Silva, N. M., Figueiredo, C. P., Frozza, R. L., Ledo, J. H., Beckman, D., Katashima, C. K., Razolli, D., Carvalho, B. M., Frazão, R., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404183 · Cited by 214
Dietary Polyphenols—Important Non-Nutrients in the Prevention of Chronic Noncommunicable Diseases. A Systematic Review
Koch, W. (2019) · Nutrients · doi:10.3390/nu11051039 · Cited by 214
Glucose Transporters in Brain: In Health and in Alzheimer’s Disease
Szablewski, L. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-160841 · Cited by 211
Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 213
The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins
Bharadwaj, P., Wijesekara, N., Liyanapathirana, M., Newsholme, P., Ittner, L. M., Fraser, P. E., & Verdile, G. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161192 · Cited by 209
Tau deletion promotes brain insulin resistance
Marciniak, E., Leboucher, A., Caron, E., Ahmed, T., Tailleux, A., Dumont, J., Issad, T., Gerhardt, E., Pagesy, P., Vileno, M., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161731 · Cited by 205
TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target
Li, R.-Y., Qin, Q., Yang, H.-C., Wang, Y.-Y., Mi, Y.-X., Yin, Y.-S., Wang, M., Yu, C.-J., & Tang, Y. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00542-y · Cited by 204
Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia
Lima, J. E. B. F., Moreira, N. C. S., & Sakamoto-Hojo, E. T. (2022) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2021.503437 · Cited by 203
Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models
Hölscher, C. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.040 · Cited by 203
Altered mitochondrial function in insulin-deficient and insulin-resistant states
Ruegsegger, G. N., Creo, A. L., Cortes, T. M., Dasari, S., & Nair, K. S. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120843 · Cited by 202
Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?
Stanley, M., Macauley, S. L., & Holtzman, D. M. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20160493 · Cited by 201
Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia
Sripetchwandee, J., Chattipakorn, N., & Chattipakorn, S. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00496 · Cited by 199
Potential Role of Glucagon-Like Peptide-1 (GLP-1) in Neuroprotection
Hölscher, C. (2012) · CNS Drugs · doi:10.2165/11635890-000000000-00000 · Cited by 198
A new way to produce hyperketonemia: Use of ketone ester in a case of Alzheimer's disease
Newport, M. T., VanItallie, T. B., Kashiwaya, Y., King, M. T., & Veech, R. L. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.01.006 · Cited by 195
Luteolin Protects against High Fat Diet-Induced Cognitive Deficits in Obesity Mice
Liu, Y., Fu, X., Lan, N., Li, S., Zhang, J., Wang, S., Li, C., Shang, Y., Huang, T., & Zhang, L. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.02.040 · Cited by 194
The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer’s Disease
Hansen, H. H., Fabricius, K., Barkholt, P., Niehoff, M. L., Morley, J. E., Jelsing, J., Pyke, C., Knudsen, L. B., Farr, S. A., & Vrang, N. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-143090 · Cited by 193
Type 2 diabetes as a risk factor for cognitive impairment: current insights
Umegaki, H. (2014) · Clinical Interventions in Aging · doi:10.2147/cia.s48926 · Cited by 189
Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics
Salameh, T. S., Rhea, E. M., Talbot, K., & Banks, W. A. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114187 · Cited by 188
Self-citation
Role of Adiponectin in Central Nervous System Disorders
Bloemer, J., Pinky, P. D., Govindarajulu, M., Hong, H., Judd, R. L., Amin, R., Moore, T., Dhanasekaran, M., Reed, M. N., & Suppiramaniam, V. D. (2018) · Neural Plasticity · doi:10.1155/2018/4593530 · Cited by 187
Intranasal Insulin for Alzheimer’s Disease
Hallschmid, M. (2021) · CNS Drugs · doi:10.1007/s40263-020-00781-x · Cited by 188
Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice
Ng, R. C.-L., Cheng, O.-Y., Jian, M., Kwan, J., Ho, P. W., Cheng, K. K. Y., Yeung, P. K. K., Zhou, L., Hoo, R. L. C., Chung, S. K., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0136-x · Cited by 189
Impaired insulin signalling and allostatic load in Alzheimer disease
Felice, F. G. D., Gonçalves, R. A., & Ferreira, S. T. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00558-9 · Cited by 183
Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration
Spielman, L. J., Little, J. P., & Klegeris, A. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.06.004 · Cited by 182
Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease
Sun, N., Akay, L. A., Murdock, M. H., Park, Y., Galiana-Melendez, F., Bubnys, A., Galani, K., Mathys, H., Jiang, X., Ng, A. P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01334-3 · Cited by 186
Self-citation
Brain insulin resistance: role in neurodegenerative disease and potential for targeting
Hölscher, C. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1738383 · Cited by 180
Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., Gupta, D., & Edison, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101979 · Cited by 179
Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease
Sun, Y., Ma, C., Sun, H. J., Wang, H., Wei, P., Zhou, Z., Wang, H., Pi, C., Shi, Y., & He, X. (2020) · Journal of Diabetes Research · doi:10.1155/2020/4981814 · Cited by 181
Self-citation
Insulin action in the brain: cell types, circuits, and diseases
Chen, W., Cai, W., Hoover, B., & Kahn, C. R. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.03.001 · Cited by 184
Recent Progress in Alzheimer’s Disease Research, Part 2: Genetics and Epidemiology
Robinson, M. J., Lee, B. Y., & Hane, F. T. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161149 · Cited by 179
Insulin Resistance as a Shared Pathogenic Mechanism Between Depression and Type 2 Diabetes
Silva, N. M. L. E., Lam, M. P., Soares, C. N., Munoz, D. P., Milev, R. V., & Felice, F. G. D. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00057 · Cited by 178
The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease
Barone, E., Domenico, F. D., Marzia Perluigi, A., & Butterfield, D. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.09.006 · Cited by 182
Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood
Lee, S.-H., Zabolotny, J. M., Huang, H., Lee, H., & Kim, Y.-B. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.011 · Cited by 176
The Complex Interactions Between Obesity, Metabolism and the Brain
Uranga, R. M., & Keller, J. N. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00513 · Cited by 174
Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism
Vercruysse, P., Vieau, D., Blum, D., Petersén, Å., & Dupuis, L. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00002 · Cited by 172
The effects of sitagliptin, a DPP-4 inhibitor, on cognitive functions in elderly diabetic patients with or without Alzheimer’s disease
Işık, A. T., Soysal, P., Yay, A., & Usarel, C. (2016) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2016.12.010 · Cited by 171
Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets
Hamzé, R., Delangre, E., Tolu, S., Moreau, M., Janel, N., Bailbé, D., & Movassat, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315287 · Cited by 171
Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease
McClean, P. L., & Hölscher, C. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.07.015 · Cited by 170
Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects
Werner, H., & LeRoith, D. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.01.020 · Cited by 167
Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer’s disease
Rad, S. K., Arya, A., Karimian, H., Madhavan, P., Rizwan, F., Koshy, S., & Prabhu, G. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s173970 · Cited by 167
The blood–brain barrier as an endocrine tissue
Banks, W. A. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0213-7 · Cited by 168
The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor–Binding Proteins in the Nervous System
LEWITT, M. S., & Boyd, G. W. (2019) · Biochemistry Insights · doi:10.1177/1178626419842176 · Cited by 166
Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine
Eid, A., Mhatre, I., & Richardson, J. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.005 · Cited by 164
Does the brain shrink as the waist expands?
Willette, A. A., & Kapogiannis, D. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2014.03.007 · Cited by 162
A Pilot Study of Exenatide Actions in Alzheimer’s Disease
Mullins, R. J., Mustapić, M., Chia, C. W., Carlson, O. D., Gulyani, S., Tran, J., Li, Y., Mattson, M. P., Resnick, S. M., Egan, J. M., et al. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190913155950 · Cited by 162
Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161
Activation of mTOR: a culprit of Alzheimer’s disease?
Cai, Z., Zhou, Y., Xiao, M., Yan, L.-J., & He, W. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s75717 · Cited by 161
Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans
Cai, W., Uribarri, J., Zhu, L., Chen, X., Swamy, S., Zhao, Z., Grosjean, F., Simonaro, C. M., Kuchel, G. A., Beeri, M. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316013111 · Cited by 160
Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review
Mittal, K., & Katare, D. P. (2016) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2016.01.021 · Cited by 161
Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes
Logan, S., Pharaoh, G. A., Marlin, M. C., Masser, D. R., Matsuzaki, S., Wronowski, B., Yeganeh, A., Parks, E. E., Premkumar, P., Farley, J. A., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.01.013 · Cited by 159
The Diabetes Drug Liraglutide Ameliorates Aberrant Insulin Receptor Localisation and Signalling in Parallel with Decreasing Both Amyloid-β Plaque and Glial Pathology in a Mouse Model of Alzheimer’s Disease
Long-Smith, C. M., Manning, S., McClean, P. L., Coakley, M. F., O’Halloran, D., Hölscher, C., & O’Neill, C. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8199-5 · Cited by 158
Glucose indices are associated with cognitive and structural brain measures in young adults
Weinstein, G., Maillard, P., Himali, J. J., Beiser, A., Au, R., Wolf, P. A., Seshadri, S. S., & DeCarli, C. S. (2015) · Neurology · doi:10.1212/wnl.0000000000001655 · Cited by 156
Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain
Perluigi, M., Pupo, G., Tramutola, A., Cini, C., Coccia, R., Barone, E., Head, E., Butterfield, D. A., & Di Domenico, F. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.007 · Cited by 155
Glucose Intolerance, Insulin Resistance, and Pathological Features of Alzheimer Disease in the Baltimore Longitudinal Study of Aging
Thambisetty, M., Metter, E. J., Yang, A., Dolan, H., Marano, C., Zonderman, A. B., Troncoso, J. C., Zhou, Y., Wong, D. F., Ferrucci, L., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.284 · Cited by 155
Aging, lifestyle and dementia
Wahl, D., Solon‐Biet, S. M., Cogger, V. C., Fontana, L., Simpson, S. J., Couteur, D. G. L., & Ribeiro, R. V. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104481 · Cited by 155
Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester
Hashim, S. A., & VanItallie, T. B. (2014) · Journal of Lipid Research · doi:10.1194/jlr.r046599 · Cited by 154
Microglial dysfunction connects depression and Alzheimer’s disease
Santos, L. E., Beckman, D., & Ferreira, S. T. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.11.011 · Cited by 154
Insulin action in the brain regulates both central and peripheral functions
Agrawal, R., Reno, C. M., Sharma, S., CHRISTENSEN, C. G., Huang, Y., & Fisher, S. J. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00642.2020 · Cited by 153
Neuroprotective and anti‐apoptotic effects of liraglutide on SH‐SY 5Y cells exposed to methylglyoxal stress
Sharma, M. K., Jalewa, J., & Hölscher, C. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12469 · Cited by 151
miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling
Kim, W., Lee, Y., McKenna, N. D., Yi, M., Šimunović, F., Wang, Y., Kong, B., Rooney, R. J., Seo, H., Stephens, R. M., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.01.021 · Cited by 151
Diabetes drugs and neurological disorders: new views and therapeutic possibilities
Patrone, C., Eriksson, O., & Lindholm, D. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70125-6 · Cited by 151
The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L., & Peng, W. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00397-x · Cited by 156
Insulin resistance and cognitive dysfunction
Ma, L., Wang, J., & Li, Y. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2015.01.027 · Cited by 150
Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model
Guo, Z., Chen, Y., Mao, Y., Zheng, T., Jiang, Y., Yan, Y., Yin, X., & Zhang, B. (2017) · Scientific Reports · doi:10.1038/srep45971 · Cited by 150
Physical Exercise Enhances Neuroplasticity and Delays Alzheimer’s Disease
Lin, T.-W., Tsai, S., & Kuo, Y. (2018) · Brain Plasticity · doi:10.3233/bpl-180073 · Cited by 151

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