{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:19:17Z","timestamp":1791980357588,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2011,2,7]],"date-time":"2011-02-07T00:00:00Z","timestamp":1297036800000},"content-version":"vor","delay-in-days":37,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["International Journal of Alzheimer's Disease"],"published-print":{"date-parts":[[2011,1]]},"abstract":"<jats:p>The most influential theory to explain the pathogenesis of Alzheimer\u2032s disease (AD) has been the \u201cAmyloid Cascade Hypothesis\u201d (ACH) first formulated in 1992. The ACH proposes that the deposition of <jats:italic>\u03b2<\/jats:italic>\u2010amyloid (A<jats:italic>\u03b2<\/jats:italic>) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late\u2010onset cases of the disease.<\/jats:p>","DOI":"10.4061\/2011\/630865","type":"journal-article","created":{"date-parts":[[2011,2,7]],"date-time":"2011-02-07T17:30:59Z","timestamp":1297099859000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["The Pathogenesis of Alzheimer\u2032s Disease: A Reevaluation of the \u201cAmyloid Cascade Hypothesis\u201d"],"prefix":"10.1155","volume":"2011","author":[{"given":"R. A.","family":"Armstrong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,2,7]]},"reference":[{"key":"e_1_2_7_1_2","first-page":"146","article-title":"On a peculiar disease of the cerebral cortex","volume":"64","author":"Alzheimer A.","year":"1907","journal-title":"Allgemeine Zeitschrift fur Psychiatrie und Psychish-Gerichtlich Medicin"},{"key":"e_1_2_7_2_2","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1001\/archneur.1985.04060100083029","article-title":"Diagnosis of Alzheimer\u2032s disease","volume":"42","author":"Khachaturian Z. S.","year":"1985","journal-title":"Archives of Neurology"},{"key":"e_1_2_7_3_2","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The consortium to establish a registry for Alzheimer\u2032s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2032s disease","volume":"41","author":"Mirra S. S.","year":"1991","journal-title":"Neurology"},{"key":"e_1_2_7_4_2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1097\/00005072-199911000-00004","article-title":"Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease","volume":"58","author":"Newell K. L.","year":"1999","journal-title":"Journal of Neuropathology and Experimental Neurology"},{"key":"e_1_2_7_5_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s100480050011","article-title":"Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis","volume":"1","author":"Graeber M. B.","year":"1997","journal-title":"Neurogenetics"},{"key":"e_1_2_7_6_2","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/0006-291X(84)91209-9","article-title":"Alzheimer\u2032s disease and Down\u2032s syndrome: sharing of a unique cerebrovascular amyloid fibril protein","volume":"122","author":"Glenner G. G.","year":"1984","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"e_1_2_7_7_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2032s disease: the amyloid cascade hypothesis","volume":"256","author":"Hardy J. A.","year":"1992","journal-title":"Science"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166\u20102236(00)02031\u20102"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2003.12.014"},{"key":"e_1_2_7_10_2","first-page":"201","article-title":"The time course of pathological events in Down\u2019s syndrome with particular reference to the involvement of microglial cells and deposits of \u03b2\/A4","volume":"1","author":"Mann D. M. A.","year":"1992","journal-title":"Neurodegeneration"},{"key":"e_1_2_7_11_2","first-page":"16","article-title":"The spatial patterns of plaques and tangles in Alzheimer\u2032s disease do not support the \u2018Cascade hypothesis\u2019","volume":"4","author":"Armstrong R. A.","year":"1993","journal-title":"Dementia"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s000180050035"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165\u20100173(03)00174\u20107"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891\u20105849(02)01021\u20103"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/353844a0"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/349704a0"},{"key":"e_1_2_7_17_2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.7638622","article-title":"Candidate gene for the chromosome 1 familial Alzheimer\u2032s disease locus","volume":"269","author":"Levy-Lahad E.","year":"1995","journal-title":"Science"},{"key":"e_1_2_7_18_2","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/375754a0","article-title":"Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2032s disease","volume":"375","author":"Sherrington R.","year":"1995","journal-title":"Nature"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440\u20101789.2000.00284.x"},{"key":"e_1_2_7_20_2","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/BF00810345","article-title":"Alzheimer\u2032s disease: identical phenotype of familial and non-familial cases","volume":"239","author":"Haupt M.","year":"1992","journal-title":"Journal of Neurology"},{"key":"e_1_2_7_21_2","first-page":"212","article-title":"Comparison of the severity of neuropathologic changes in familial add sporadic Alzheimer\u2032s disease","volume":"7","author":"Nochlin D.","year":"1993","journal-title":"Alzheimer Disease and Associated Disorders"},{"key":"e_1_2_7_22_2","first-page":"249","article-title":"Association between genetic and environmental factors and the risk of Alzheimer\u2032s disease","volume":"46","author":"Styczy\u0144ska M.","year":"2008","journal-title":"Folia Neuropathologica"},{"key":"e_1_2_7_23_2","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/373523a0","article-title":"Alzheimer-type neuropathology in transgenic mice overexpressing V717F \u03b2-amyloid precursor protein","volume":"373","author":"Games D.","year":"1995","journal-title":"Nature"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304\u20103940(92)90408\u2010Y"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2003.10.008"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1385\/NMM:4:1\u20102:49"},{"key":"e_1_2_7_27_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/nm0495-365","article-title":"Tau protein directly interacts with the amyloid \u03b2-protein precursor: implications for Alzheimer\u2032s disease","volume":"1","author":"Smith M. A.","year":"1995","journal-title":"Nature Medicine"},{"key":"e_1_2_7_28_2","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1111\/j.1471-4159.1993.tb13388.x","article-title":"\u03b2-amyloid protein precursor and \u03c4 mRNA levels versus \u03b2-amyloid plaque and neurofibrillary tangles in the aged human brain","volume":"60","author":"Oyama F.","year":"1993","journal-title":"Journal of Neurochemistry"},{"key":"e_1_2_7_29_2","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/0896-6273(95)90232-5","article-title":"\u03b2-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding","volume":"14","author":"Busciglio J.","year":"1995","journal-title":"Neuron"},{"key":"e_1_2_7_30_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3233\/JAD-2004-6501","article-title":"Interaction of Alzheimer\u2032s disease amyloid \u03b2 peptide fragment 25-35 with tau protein, and with a tau peptide containing the microtubule binding domain","volume":"6","author":"P\u00e9rez M.","year":"2004","journal-title":"Journal of Alzheimer\u2032s Disease"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440\u20101789.2002.00446.x"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304\u20103940(93)90398\u20105"},{"key":"e_1_2_7_33_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/00001756-199412300-00041","article-title":"Increased numbers of \u03b2APP-immunoreactive neurones in the entorhinal cortex after head injury","volume":"6","author":"McKenzie J. E.","year":"1994","journal-title":"NeuroReport"},{"key":"e_1_2_7_34_2","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1136\/jnnp.57.4.419","article-title":"\u03b2 amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer\u2032s disease","volume":"57","author":"Roberts G. W.","year":"1994","journal-title":"Journal of Neurology Neurosurgery and Psychiatry"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20108993(93)91202\u20104"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140\u20106736(92)91780\u2010C"},{"key":"e_1_2_7_37_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1007\/BF00296796","article-title":"\u03b1B-crystallin is present in reactive glia in Creutzfeldt-Jakob disease","volume":"83","author":"Renkawek K.","year":"1992","journal-title":"Acta Neuropathologica"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169\u2010328X(91)90108\u2010A"},{"key":"e_1_2_7_39_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/0006-8993(91)91558-I","article-title":"Expression of APP in the early stage of brain damage","volume":"563","author":"Kawarabayashi T.","year":"1991","journal-title":"Brain Research"},{"key":"e_1_2_7_40_2","unstructured":"KalariaR. N. BhattS. U. PerryG. andLustW. D. The amyloid precursor protein in ischaemic brain injury and chronic hypoperfusion Proceedings of the 7th International Study Group on Pharm Mem Dis Assoc with Aging 1993 291\u2013294."},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304\u20103940(94)90344\u20101"},{"key":"e_1_2_7_42_2","first-page":"88","article-title":"Amyloid, dementia and Alzheimer\u2032s disease","volume":"5","author":"Hyman B. T.","year":"1992","journal-title":"Current Opinion in Neurology and Neurosurgery"},{"key":"e_1_2_7_43_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/BF00454896","article-title":"The spatial patterns of \u03b2\/A4 deposit subtypes in Alzheimer\u2032s disease","volume":"86","author":"Armstrong R. A.","year":"1993","journal-title":"Acta Neuropathologica"},{"key":"e_1_2_7_44_2","first-page":"1","article-title":"Plaques and tangles and the pathogenesis of Alzheimer\u2032s disease","volume":"44","author":"Armstrong R. A.","year":"2006","journal-title":"Folia Neuropathologica"},{"key":"e_1_2_7_45_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/0470846542.ch3","article-title":"Ageing, stress and the brain","volume":"242","author":"Carroll B. J.","year":"2002","journal-title":"Novartis Foundation Symposium"},{"key":"e_1_2_7_46_2","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/S0002-9440(10)63235-X","article-title":"Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer\u2032s disease","volume":"164","author":"Schmitz C.","year":"2004","journal-title":"American Journal of Pathology"},{"key":"e_1_2_7_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440\u20101789.2005.00605.x"},{"key":"e_1_2_7_48_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0974\u201004.2004"},{"key":"e_1_2_7_49_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1297.001"}],"container-title":["International Journal of Alzheimer\u2019s Disease"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/ijad\/2011\/630865.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/ijad\/2011\/630865.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.4061\/2011\/630865","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T08:18:36Z","timestamp":1718698716000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.4061\/2011\/630865"}},"subtitle":[],"editor":[{"given":"Alan P.","family":"Hudson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,1]]},"references-count":49,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,1]]}},"alternative-id":["10.4061\/2011\/630865"],"URL":"https:\/\/doi.org\/10.4061\/2011\/630865","archive":["Portico"],"relation":{},"ISSN":["2090-8024","2090-0252"],"issn-type":[{"value":"2090-8024","type":"print"},{"value":"2090-0252","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1]]},"assertion":[{"value":"2010-11-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-01-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-02-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"630865"}}