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dc.contributor.authorHunter, Sallyen
dc.contributor.authorSmailagic, Nadjijaen
dc.contributor.authorBrayne, Carolen
dc.date.accessioned2018-11-17T00:30:58Z
dc.date.available2018-11-17T00:30:58Z
dc.date.issued2018-12en
dc.identifier.issn0014-2972
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285351
dc.description.abstractThe amyloid cascade hypothesis (ACH) has dominated strategy in dementia research for decades despite evidence of its limitations including known heterogeneity of the dementia syndrome in the population and the narrow focus on a single molecule - the amyloid beta protein (Aβ) as causal for all Alzheimer-type dementia. Other hypotheses relevant to Aβ are the presenilin (PS) hypothesis (PSH) relating to the involvement of PS in the generation of Aβ, and the amyloid precursor protein (APP) matrix approach (AMA), relating to the complex and dynamic breakdown of APP, from which Aβ derives. In this article we explore perspectives relating to complex disorders occurring mainly in older populations through a detailed case study of the role of Aβ in AD. Scrutiny of the evidence generated so far reveals and a lack of understanding of the wider APP proteolytic system and how narrow research into the dementia syndrome has been to date. Confounding factors add significant limitations to the understanding of the current evidence base. A better characterisation of the entire APP proteolytic system in the human brain is urgently required to place Aβ in its complex physiological context. From a molecular perspective, a combination of the alternative hypotheses, the PSH and the AMA may better describe the complexity of the APP proteolytic system leading to new therapeutic approaches. The reductionist approach is widespread throughout biomedical research and this example highlights how neglect of complexity can undermine investigations of complex disorders, particularly those arising in the oldest in our populations.
dc.description.sponsorshipSH was supported by an NIHR Senior Investigator Award awarded to CB. SH is also supported by a grant from the Paul G. Allen Family Foundation. NS is supported by EPAD. The funders were not involved in any part of the manuscript preparation.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherWiley-Blackwell
dc.subjectHumansen
dc.subjectAlzheimer Diseaseen
dc.subjectBiomedical Researchen
dc.subjectClinical Trials as Topicen
dc.subjectAmyloid beta-Peptidesen
dc.subjectBiomarkersen
dc.titleAβ and the dementia syndrome: Simple versus complex perspectives.en
dc.typeArticle
prism.issueIdentifier12en
prism.publicationDate2018en
prism.publicationNameEuropean journal of clinical investigationen
prism.startingPagee13025
prism.volume48en
dc.identifier.doi10.17863/CAM.32719
dcterms.dateAccepted2018-09-06en
rioxxterms.versionofrecord10.1111/eci.13025en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-12en
dc.contributor.orcidHunter, Sally [0000-0002-8063-6556]
dc.contributor.orcidBrayne, Carol [0000-0001-5307-663X]
dc.identifier.eissn1365-2362
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idPaul G Allen Family Foundation (12076)
rioxxterms.freetoread.startdate2019-09-24


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