{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:02:52Z","timestamp":1789668172397,"version":"4.0.1"},"reference-count":488,"publisher":"SAGE Publications","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,6,29]]},"abstract":"<jats:p>Almost 115 years ago, Alois Alzheimer described Alzheimer\u2019s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.<\/jats:p>","DOI":"10.3233\/jad-210234","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T14:01:59Z","timestamp":1621346519000},"page":"71-105","source":"Crossref","is-referenced-by-count":42,"title":["Insulin Resistance as a Common Link Between Current Alzheimer\u2019s Disease Hypotheses"],"prefix":"10.1177","volume":"82","author":[{"given":"Su\u00e9len Santos","family":"Alves","sequence":"first","affiliation":[{"name":"Department of Neurosciences and Behavioral Sciences, Ribeir\u00e3o Preto Medical School - University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui Milton Patr\u00edcio da","family":"Silva-Junior","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ribeir\u00e3o Preto Medical School \u2013University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"},{"name":"Department of Physiology, Ribeir\u00e3o Preto Medical School \u2013 University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Servilha-Menezes","sequence":"additional","affiliation":[{"name":"Department of Physiology, Ribeir\u00e3o Preto Medical School \u2013 University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Homolak","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia"},{"name":"Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melita","family":"\u0160alkovi\u0107-Petri\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia"},{"name":"Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norberto","family":"Garcia-Cairasco","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Behavioral Sciences, Ribeir\u00e3o Preto Medical School - University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"},{"name":"Department of Physiology, Ribeir\u00e3o Preto Medical School \u2013 University of S\u00e3o Paulo (FMRP-USP), Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-210234_ref1","first-page":"177","article-title":"Uber eine eigenartige Erkrankung der Hirnrinde","volume":"18","author":"Alzheimer","year":"1907","journal-title":"Zentralbl Nervenh Psychiatr"},{"key":"10.3233\/JAD-210234_ref2","doi-asserted-by":"crossref","first-page":"3740461","DOI":"10.1155\/2018\/3740461","article-title":"Current concepts of neurodegenerative mechanisms in Alzheimer\u2019s disease","volume":"2018","author":"Magalingam","year":"2018","journal-title":"Biomed Res Int"},{"key":"10.3233\/JAD-210234_ref3","first-page":"1","article-title":"History and progress of hypotheses and clinical trials for Alzheimer\u2019s disease","volume":"4","author":"Liu","year":"2019","journal-title":"Signal Transduct Target Ther"},{"key":"10.3233\/JAD-210234_ref4","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1001\/jamaneurol.2019.1424","article-title":"Association of amyloid and tau with cognition in preclinical Alzheimer\u2019s disease: A longitudinal study","volume":"76","author":"Hanseeuw","year":"2019","journal-title":"JAMA Neurol"},{"key":"10.3233\/JAD-210234_ref5","first-page":"101","article-title":"The discovery of Alzheimer\u2019s disease","volume":"5","author":"Hippius","year":"2003","journal-title":"Clin Res"},{"key":"10.3233\/JAD-210234_ref6","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"10.3233\/JAD-210234_ref7","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/23571","article-title":"Alois Alzheimer and the amyloid debate","volume":"400","author":"Davis","year":"1999","journal-title":"Nature"},{"key":"10.3233\/JAD-210234_ref8","unstructured":"Alzheimer\u2019s Disease International (2019) World Alzheimer Report 2019: Attitudes to dementia. 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