{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:34:49Z","timestamp":1787942089631,"version":"build-2784847793"},"reference-count":112,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T00:00:00Z","timestamp":1517184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["SAF2017-84283-R"],"award-info":[{"award-number":["SAF2017-84283-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid \u03b2 peptide (A\u03b2), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of A\u03b2 production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that A\u03b242 generated in the brain would impact negatively on the hypothalamus, accelerating the \u201cperipheral\u201d symptomatology of AD. In this situation, A\u03b242 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.<\/jats:p>","DOI":"10.3390\/ph11010011","type":"journal-article","created":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T07:46:20Z","timestamp":1517211980000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["The Implication of the Brain Insulin Receptor in Late Onset Alzheimer\u2019s Disease Dementia"],"prefix":"10.3390","volume":"11","author":[{"given":"Jaume","family":"Folch","sequence":"first","affiliation":[{"name":"Departament de Bioqu\u00edmica i Biotecnologia, Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miren","family":"Ettcheto","sequence":"additional","affiliation":[{"name":"Departament de Bioqu\u00edmica i Biotecnologia, Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriol","family":"Busquets","sequence":"additional","affiliation":[{"name":"Departament de Bioqu\u00edmica i Biotecnologia, Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"S\u00e1nchez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Unitat de Farm\u00e0cia, Tecnologia Farmac\u00e8utica i Fisico-qu\u00edmica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona E-08028, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Castro-Torres","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Departament de Biologia Cel\u00b7lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Laboratorio de Regeneraci\u00f3n y Desarrollo Neural, Instituto de Neurobiolog\u00eda, Departamento de Biolog\u00eda Celular y Molecular, Centro Universitario de Ciencias Biol\u00f3gicas y Agropecuarias, Universidad de Guadalajara, Zapopan 44600, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Verdaguer","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Departament de Biologia Cel\u00b7lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Manzine","sequence":"additional","affiliation":[{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"},{"name":"Department of Gerontology, Federal University of S\u00e3o Carlos (UFSCar), S\u00e3o Carlos 13565-905, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saghar","family":"Poor","sequence":"additional","affiliation":[{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Unitat de Farm\u00e0cia, Tecnologia Farmac\u00e8utica i Fisico-qu\u00edmica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona E-08028, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Olloquequi","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Biom\u00e9dicas, Facultad de Ciencias de la Salud, Universidad Aut\u00f3noma de Chile, Talca 3460000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Beas-Zarate","sequence":"additional","affiliation":[{"name":"Laboratorio de Regeneraci\u00f3n y Desarrollo Neural, Instituto de Neurobiolog\u00eda, Departamento de Biolog\u00eda Celular y Molecular, Centro Universitario de Ciencias Biol\u00f3gicas y Agropecuarias, Universidad de Guadalajara, Zapopan 44600, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8345-1859","authenticated-orcid":false,"given":"Carme","family":"Auladell","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"},{"name":"Departament de Biologia Cel\u00b7lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1229-5956","authenticated-orcid":false,"given":"Antoni","family":"Camins","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain"},{"name":"Departament de Farmacologia, Toxicologia i Qu\u00edmica Terap\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Av. Joan XXIII 27\/31, E-08028 Barcelona, Spain"},{"name":"Institut de Neuroci\u00e8ncies, Universitat de Barcelona, E-08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2016). 2016 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 12, 459\u2013509.","DOI":"10.1016\/j.jalz.2016.03.001"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s12035-014-9053-6","article-title":"Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer\u2019s Disease: Understanding the Therapeutics Strategies","volume":"53","author":"Kamat","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/ca.980080612","article-title":"An English translation of Alzheimer\u2019s 1907 paper, \u201cUber eine eigenartige Erkrankung der Hirnrinde\u201d","volume":"8","author":"Alzheimer","year":"1995","journal-title":"Clin. Anat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1258\/jmb.2010.010037","article-title":"Alois Alzheimer (1864\u20131915) and the Alzheimer syndrome","volume":"19","author":"Vishal","year":"2011","journal-title":"J. Med. Biogr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15056","DOI":"10.1038\/nrdp.2015.56","article-title":"Alzheimer\u2019s disease","volume":"1","author":"Masters","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/nrneurol.2012.112","article-title":"Alzheimer disease: Insulin resistance and AD: Extending the translational path","volume":"8","author":"Craft","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S2215-0366(15)00454-X","article-title":"Development of interventions for the secondary prevention of Alzheimer\u2019s dementia: The European Prevention of Alzheimer\u2019s Dementia (EPAD) project","volume":"3","author":"Ritchie","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer\u2019s disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S1474-4422(10)70119-8","article-title":"Alzheimer\u2019s disease: Clinical trials and drug development","volume":"9","author":"Mangialasche","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/nm.2460","article-title":"Resolving controversies on the path to Alzheimer\u2019s therapeutics","volume":"17","author":"Selkoe","year":"2011","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00401-015-1386-3","article-title":"Amyloid \u03b2 oligomers in Alzheimer\u2019s disease pathogenesis, treatment, and diagnosis","volume":"129","author":"Viola","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Moser, V.A., and Pike, C.J. (2017). Obesity Accelerates Alzheimer-Related Pathology in APOE4but not APOE3Mice. eNeuro, 4.","DOI":"10.1523\/ENEURO.0077-17.2017"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1212\/WNL.50.1.164","article-title":"Cerebrospinal fluid and plasma insulin levels in Alzheimer\u2019s disease: Relationship to severity of dementia and apolipoprotein E genotype","volume":"50","author":"Craft","year":"1998","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuron.2017.09.003","article-title":"Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes","volume":"96","author":"Zhao","year":"2017","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Neth, B.J., and Craft, S. (2017). Insulin Resistance and Alzheimer's Disease: Bioenergetic Linkages. Front. Aging Neurosci.","DOI":"10.3389\/fnagi.2017.00345"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s40265-016-0674-0","article-title":"Insulin Resistance and Neurodegeneration: Progress towards the Development of New Therapeutics for Alzheimer\u2019s disease","volume":"77","year":"2017","journal-title":"Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.2337\/dbi15-0011","article-title":"A Key Role of Insulin Receptors in Memory","volume":"64","author":"Benedict","year":"2015","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/joim.12191","article-title":"Clinical trials and late-stage drug development for Alzheimer\u2019s disease: An appraisal from 1984 to 2014","volume":"275","author":"Chneider","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nrd1958","article-title":"Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond","volume":"5","author":"Lipton","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.2741\/4285","article-title":"An update on drug treatment options of Alzheimer\u2019s disease","volume":"19","author":"Allgaier","year":"2014","journal-title":"Front. Biosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s007020050068","article-title":"Insulin and insulin receptors in the brain in aging and in sporadic Alzheimer\u2019s disease","volume":"105","author":"Frolich","year":"1998","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.1749-6632.1999.tb07839.x","article-title":"A disturbance of the neuronal insulin receptor signal transduction in sporadic Alzheimer\u2019s disease","volume":"893","author":"Frolich","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejphar.2004.02.049","article-title":"Glucose metabolism and insulin receptor signal transduction in Alzheimer disease","volume":"490","author":"Hoyer","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1007\/s00702-006-0592-5","article-title":"Alois Alzheimer revisited: Differences in origin of the disease carrying his name","volume":"113","author":"Maurer","year":"2006","journal-title":"J. Neural Transm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1016\/0024-3205(94)00377-7","article-title":"Neurodegeneration, Alzheimer\u2019s disease, and beta-amyloid toxicity","volume":"55","author":"Hoyer","year":"1994","journal-title":"Life Sci."},{"key":"ref_29","first-page":"S26","article-title":"How does brain insulin resistance develop in Alzheimer\u2019s disease?","volume":"10","author":"Lourenco","year":"2014","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.2337\/db13-1954","article-title":"Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer Disease","volume":"63","author":"Ferreira","year":"2014","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3233\/JAD-2005-7106","article-title":"Review of insulin and insulin-like growth factor expresion, signaling, and malfunction in the central nervous system: Relevance to alzheimer\u2019s disease","volume":"7","author":"Wands","year":"2005","journal-title":"J. Alzheimer Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2174\/156720512799015037","article-title":"Brain insulin resistance and deficiency as therapeutic targets in Alzheimer\u2019s disease","volume":"9","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1212\/WNL.53.9.1937","article-title":"Diabetes mellitus and the risk of dementia: The Rotterdam Study","volume":"53","author":"Ott","year":"1999","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1212\/WNL.0b013e3181ffe4f6","article-title":"Insulin metabolism and the risk of Alzheimer disease: The Rotterdam Study","volume":"75","author":"Schrijvers","year":"2010","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1172\/JCI59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF1 resistance, IRS1 dysregulation, and cognitive decline","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nrn4019","article-title":"Hippocampal insulin resistance and cognitive dysfunction","volume":"16","author":"Biessels","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1126\/science.1104344","article-title":"Diabetes, obesity, and the brain","volume":"307","author":"Schwartz","year":"2005","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.nlm.2011.08.005","article-title":"Brain insulin signaling a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes","volume":"96","author":"McNay","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_39","first-page":"4","article-title":"Brain insulin signaling and Alzheimer\u2019s disease: Current evidente and future direction","volume":"46","author":"Craft","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3233\/JAD-2012-112192","article-title":"Intrahippocampal administration of amyloid-\u03b2(1-42) oligomers acutely impairs spatial working memory, insulin signaling, and hippocampal metabolism","volume":"30","author":"McNay","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7332","DOI":"10.3390\/nu7095341","article-title":"Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer\u2019s Disease: Impacts on Cognitive Decline","volume":"7","author":"Walker","year":"2015","journal-title":"Nutrients"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.2337\/db15-0596","article-title":"Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity","volume":"64","author":"Grillo","year":"2015","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neurobiolaging.2005.08.021","article-title":"Insulin resistance syndrome and Alzheimer\u2019s disease: Age- and obesity-related effects on memory, amyloid, and inflammation","volume":"26","author":"Craft","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1089\/ars.2016.6759","article-title":"The Triangle of Death in Alzheimer\u2019s Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics","volume":"26","author":"Barone","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3233\/JAD-2005-7107","article-title":"Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer\u2019s disease\u2014Is this type 3 diabetes?","volume":"7","author":"Steen","year":"2005","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"723","DOI":"10.2174\/1567205012666150710115506","article-title":"Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer\u2019s Disease","volume":"12","author":"Nuzzo","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"210","DOI":"10.2337\/ds16-0041","article-title":"Type 2 Diabetes, Cognition, and Dementia in Older Adults: Toward a Precision Health Approach","volume":"29","author":"Cholerton","year":"2016","journal-title":"Diabetes Spectr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1016\/S0140-6736(12)60360-2","article-title":"Diabetes and cognitive dysfunction","volume":"379","author":"McCrimmon","year":"2012","journal-title":"Lancet"},{"key":"ref_49","first-page":"34839","article-title":"Brain insulin receptors and spatial memory","volume":"274","author":"Xu","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s11011-016-9806-1","article-title":"The rise and fall of insulin signaling in Alzheimer's disease","volume":"31","author":"Chami","year":"2016","journal-title":"Metab Brain Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1093\/cercor\/bht101","article-title":"Altered expression of diabetes-related genes in Alzheimer\u2019s disease brains: The Hisayama study","volume":"24","author":"Hokama","year":"2014","journal-title":"Cereb. Cortex"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1586\/14737175.2013.864824","article-title":"Connecting type 2 diabetes to Alzheimer's disease","volume":"13","year":"2013","journal-title":"Expert Rev. Neurother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9078","DOI":"10.1523\/JNEUROSCI.1071-09.2009","article-title":"Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Suppression by omega-3 fatty acids and curcumin","volume":"29","author":"Ma","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s00401-014-1328-5","article-title":"Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer\u2019s disease and tauopathies","volume":"128","author":"Yarchoan","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/272827a0","article-title":"Insulin receptors are widely distributed in the central nervous system of the rat","volume":"5656","author":"Havrankova","year":"1978","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/joim.12534","article-title":"Insulin signalling in Alzheimer\u2019s disease and diabetes: From epidemiology to molecular links","volume":"280","author":"Ribe","year":"2016","journal-title":"J. Intern. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.bbadis.2016.08.018","article-title":"Is Alzheimer\u2019s disease a Type 3 Diabetes? A critical appraisal","volume":"1863","author":"Kandimalla","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.trsl.2016.12.005","article-title":"Insulin resistance in Alzheimer\u2019s disease","volume":"183","author":"Diehl","year":"2017","journal-title":"Transl. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/path.2912","article-title":"Deficient brain insulin signalling pathway in Alzheimer\u2019s disease and diabetes","volume":"225","author":"Liu","year":"2011","journal-title":"J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1042\/BST0331041","article-title":"Increased risk of Alzheimer\u2019s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?","volume":"33","author":"Biessels","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1084\/jem.20160493","article-title":"Changes in insulin and insulin signaling in Alzheimer\u2019s disease: Cause or consequence?","volume":"213","author":"Stanley","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.psyneuen.2017.05.004","article-title":"Insulin signaling: An opportunistic target to minify the risk of Alzheimer\u2019s disease","volume":"83","author":"Pardeshi","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1073\/pnas.0308724101","article-title":"Role for neuronal insulin resistance in neurodegenerative diseases","volume":"101","author":"Schubert","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.2337\/diabetes.54.12.3343","article-title":"Peripheral hyperinsulinemia promotes tau phosphorylation in vivo","volume":"54","author":"Freude","year":"2005","journal-title":"Diabetes"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pneurobio.2003.08.002","article-title":"Insulin-like growth factor-1 and post-ischemic brain injury","volume":"70","author":"Guan","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1093\/brain\/awx256","article-title":"Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons","volume":"140","author":"Rabano","year":"2017","journal-title":"Brain"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.neuron.2016.12.020","article-title":"GLUT4 Mobilization Supports Energetic Demands of Active Synapses","volume":"93","author":"Ashrafi","year":"2017","journal-title":"Neuron"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1523\/JNEUROSCI.1700-16.2016","article-title":"Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory","volume":"36","author":"McNay","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.yhbeh.2016.12.012","article-title":"Quercetin ameliorates chronic unpredicted stress-mediated memory dysfunction in male Swiss albino mice by attenuating insulin resistance and elevating hippocampal GLUT4 levels independent of insulin receptor expression","volume":"89","author":"Mehta","year":"2017","journal-title":"Horm. Behav."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.neuint.2017.04.020","article-title":"Bidirectional interactions between diabetes and Alzheimer\u2019s disease","volume":"108","author":"Shinohara","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3349\/ymj.2017.58.3.479","article-title":"Metabolism-Centric Overview of the Pathogenesis of Alzheimer\u2019s disease","volume":"58","author":"Kang","year":"2017","journal-title":"Yonsei Med. J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuroscience.2016.06.049","article-title":"Gender differences of peripheral plasma and liver metabolic profiling in APP\/PS1 transgenic AD mice","volume":"332","author":"Wu","year":"2016","journal-title":"Neuroscience"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.2337\/db12-0670","article-title":"Amyloid-\u03b2 induces hepatic insulin resistance in vivo via JAK2","volume":"62","author":"Zhang","year":"2013","journal-title":"Diabetes"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.2337\/db11-0499","article-title":"Amyloid-\u03b2 induces hepatic insulin resistance by activating JAK2\/STAT3\/SOCS-1 signaling pathway","volume":"61","author":"Zhang","year":"2012","journal-title":"Diabetes"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13629","DOI":"10.1523\/JNEUROSCI.1353-14.2014","article-title":"Alzheimer\u2019s disease-like pathology induced by amyloid-\u03b2 oligomers in nonhuman primates","volume":"34","author":"Batista","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"190","DOI":"10.15252\/emmm.201404183","article-title":"Alzheimer-associated A\u03b2 oligomers impact the central nervous system to induce peripheral metabolic deregulation","volume":"7","author":"Clarke","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"843","DOI":"10.3233\/JAD-131865","article-title":"Acute Exposure of the Mediobasal Hypothalamus to Amyloid-\u03b225\u201335 Perturbs Hepatic Glucose Metabolism","volume":"46","author":"Knight","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_78","first-page":"53","article-title":"The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer\u2019s Disease","volume":"68","year":"2016","journal-title":"Rev. Investig. Clin."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jalz.2008.10.004","article-title":"Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer\u2019s disease","volume":"5","author":"Roher","year":"2009","journal-title":"Alzheimers Dement."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"871","DOI":"10.3233\/JAD-2011-110884","article-title":"Amyloid-\u03b242 activates the expression of BACE1 through the JNK pathway","volume":"27","author":"Guglielmotto","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/j.1474-9726.2012.00854.x","article-title":"A\u03b21\u201342-mediated downregulation of Uch-L1 is dependent on NF-\u03baB activation and impaired BACE1 lysosomal degradation","volume":"11","author":"Guglielmotto","year":"2012","journal-title":"Aging Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.4161\/auto.30001","article-title":"A\u03b21\u201342 monomers or oligomers have different effects on autophagy and apoptosis","volume":"10","author":"Guglielmotto","year":"2014","journal-title":"Autophagy"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10710","DOI":"10.1523\/JNEUROSCI.0433-14.2014","article-title":"Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes","volume":"34","author":"Crouch","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1007\/s00125-016-3960-1","article-title":"Neuronal human BACE1 knockin induces systemic diabetes in mice","volume":"59","author":"Dekeryte","year":"2016","journal-title":"Diabetologia"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1042\/BJ20110512","article-title":"Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice","volume":"441","author":"Meakin","year":"2012","journal-title":"Biochem. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1016\/j.euroneuro.2014.06.008","article-title":"Type 3 diabetes is sporadic Alzheimer\u2019s disease: Mini-review","volume":"24","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"483","DOI":"10.3233\/JAD-2009-1155","article-title":"Insulin is a two-edged knife on the brain","volume":"18","author":"Cardoso","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3233\/JAD-2006-10113","article-title":"Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer\u2019s disease","volume":"10","author":"Tong","year":"2006","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/j.1463-1326.2011.01490.x","article-title":"Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism","volume":"14","author":"Ott","year":"2012","journal-title":"Diabetes Obes. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2217\/ahe.11.89","article-title":"Early intranasal insulin therapy halts progression of neurodegeneration: Progress in Alzheimer\u2019s disease therapeutics","volume":"8","year":"2012","journal-title":"Aging Health"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/13543784.2017.1265504","article-title":"Pioglitazone for the treatment of Alzheimer\u2019s disease","volume":"26","author":"Galimberti","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1007\/s10495-016-1280-z","article-title":"Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-\u03baB","volume":"21","author":"Zhang","year":"2016","journal-title":"Apoptosis"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.neurobiolaging.2009.10.009","article-title":"Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease","volume":"32","author":"Sato","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_94","first-page":"497","article-title":"Drugs developed for treatment of diabetes show protective effects in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"66","year":"2014","journal-title":"Sheng Li Xue Bao"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.95.11.6448","article-title":"Diffusible, nonfibrillar ligands derived from Abeta1\u201342 are potent central nervous system neurotoxins","volume":"95","author":"Lambert","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.1007\/s10875-014-0032-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease: From pathogenesis to a therapeutic target","volume":"34","author":"Pimplikar","year":"2014","journal-title":"J. Clin. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s12035-013-8457-z","article-title":"Autophagy modulation for Alzheimer\u2019s disease therapy","volume":"48","author":"Zhu","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.phrs.2014.02.008","article-title":"Temsirolimus promotes autophagic clearance of amyloid-\u03b2 and provides protective effects in cellular and animal models of Alzheimer\u2019s disease","volume":"81","author":"Jiang","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1080\/14737175.2017.1244482","article-title":"Targeting mTOR to reduce Alzheimer-related cognitive decline: From current hits to future therapies","volume":"17","author":"Tramutola","year":"2017","journal-title":"Expert Rev. Neurother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1532-5415.2009.02067.x","article-title":"Pioglitazone improved cognition in a pilot study on patients with Alzheimer\u2019s disease and mild cognitive impairment with diabetes mellitus","volume":"57","author":"Hanyu","year":"2009","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1001\/archneurol.2010.229","article-title":"A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease","volume":"68","author":"Geldmacher","year":"2011","journal-title":"Arch. Neurol."},{"key":"ref_102","first-page":"92","article-title":"Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer\u2019s disease","volume":"3","author":"Atkinson","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1523\/JNEUROSCI.21-08-02561.2001","article-title":"Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling","volume":"21","author":"Gasparini","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3233\/JAD-2005-8304","article-title":"Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer\u2019s disease: Link to brain reductions in acetylcholine","volume":"8","author":"Rivera","year":"2005","journal-title":"J. Alzheimers Dis."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Farr, S.A., Salameh, T.S., Niehoff, M.L., Rhea, E.M., Morley, J.E., Hanson, A.J., Hansen, K.M., and Craft, S. (2017). Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. Int. J. Obes.","DOI":"10.1038\/ijo.2017.231"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1172\/JCI116773","article-title":"Saturable transport of insulin from plasma into the central-nervous-system of dogs in-vivo\u2014A mechanism for regulated insulin delivery to the brain","volume":"92","author":"Baura","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.tem.2005.01.008","article-title":"The role of insulin receptor signaling in the brain","volume":"16","author":"Plum","year":"2005","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.3233\/JAD-161256","article-title":"Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer\u2019s Disease Biomarkers: A Pilot Clinical Trial","volume":"57","author":"Craft","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1001\/archneurol.2011.233","article-title":"Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial","volume":"69","author":"Craft","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1586\/14737140.2014.864562","article-title":"Temsirolimus for advanced renal cellcarcinoma","volume":"14","author":"Bergmann","year":"2014","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1634\/theoncologist.2009-0178","article-title":"FDA approval summary: Temsirolimus as treatment foradvanced renal cell carcinoma","volume":"15","author":"Kwitkowski","year":"2010","journal-title":"Oncologist"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/nrneurol.2017.111","article-title":"A systemic view of Alzheimer disease\u2014Insights from amyloid-\u03b2 metabolism beyond the brain","volume":"13","author":"Wang","year":"2017","journal-title":"Nat. Rev. Neurol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/11\/1\/11\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:52:53Z","timestamp":1760194373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/11\/1\/11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,29]]},"references-count":112,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["ph11010011"],"URL":"https:\/\/doi.org\/10.3390\/ph11010011","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,29]]}}}