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      The amyloid hypothesis of Alzheimer's disease at 25 years

      1 , , 2

      EMBO Molecular Medicine

      John Wiley and Sons Inc.

      , Alzheimer, genetics, cell biology, treatment, Neuroscience

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          Abstract

          Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease ( AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid ( CSF) Aβ42 and amyloid‐ PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

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          Most cited references 115

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          The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

           D. Selkoe,  John Hardy (2002)
          It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.
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            Neuropathological stageing of Alzheimer-related changes.

             E Braak,  H Braak (1990)
            Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
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              Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

              Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                29 March 2016
                June 2016
                : 8
                : 6 ( doiID: 10.1002/emmm.v8.6 )
                : 595-608
                Affiliations
                [ 1 ] Ann Romney Center for Neurologic Diseases Department of NeurologyBrigham and Women's Hospital and Harvard Medical School Boston MAUSA
                [ 2 ] Reta Lila Weston Institute and Department of Molecular NeuroscienceUCL Institute of Neurology LondonUK
                Author notes
                [* ]Corresponding author. Tel: +44 203 108 7466; E‐mail: j.hardy@ 123456ucl.ac.uk
                [†]

                These authors contributed equally to this work

                Article
                EMMM201606210
                10.15252/emmm.201606210
                4888851
                27025652
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Counts
                Pages: 14
                Product
                Funding
                Funded by: National Institute on Aging
                Award ID: AG06173
                Award ID: AG015379
                Funded by: MRC
                Funded by: ARUK
                Funded by: Wellcome Trust
                Categories
                Review
                Review
                Custom metadata
                2.0
                emmm201606210
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:16.09.2016

                Molecular medicine

                , neuroscience, treatment, cell biology, genetics, alzheimer

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