Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease

Read this article at

Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aβ) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of Aβ deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aβ oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for Aβ in AD. We conclude it is essential to expand our view of pathogenesis beyond Aβ and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.

      Related collections

      Most cited references 225

      • Record: found
      • Abstract: found
      • Article: not found

      Power failure: why small sample size undermines the reliability of neuroscience.

      A study with low statistical power has a reduced chance of detecting a true effect, but it is less well appreciated that low power also reduces the likelihood that a statistically significant result reflects a true effect. Here, we show that the average statistical power of studies in the neurosciences is very low. The consequences of this include overestimates of effect size and low reproducibility of results. There are also ethical dimensions to this problem, as unreliable research is inefficient and wasteful. Improving reproducibility in neuroscience is a key priority and requires attention to well-established but often ignored methodological principles.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        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.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Alzheimer's disease is a synaptic failure.

           D. Selkoe (2002)
          In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.
            Bookmark

            Author and article information

            Affiliations
            [ ]Garvan Institute of Medical Research, Neuroscience Department, Neurodegenerative Disorders Laboratory, 384 Victoria Street, Darlinghurst, NSW 2010 Australia
            [ ]Faculty of Medicine, University of New South Wales, Sydney, Australia
            [ ]Research School of Biology, Australian National University, Canberra, Australia
            Contributors
            g.morris@garvan.org.au
            ian.clark@anu.edu.au
            brycevissel@gmail.com
            Journal
            Acta Neuropathol Commun
            Acta Neuropathol Commun
            Acta Neuropathologica Communications
            BioMed Central (London )
            2051-5960
            18 September 2014
            18 September 2014
            2014
            : 2
            : 1
            25231068 4207354 135 10.1186/s40478-014-0135-5
            © Morris et al.; licensee BioMed Central Ltd. 2014

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Review
            Custom metadata
            © The Author(s) 2014

            Comments

            Comment on this article