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      Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics

      1 , 2 , 3 , 1 , 2 , 3 , 4
      Annual Review of Neuroscience
      Annual Reviews

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          Abstract

          Ten years of remarkable progress in understanding the fundamental biochemistry of Alzheimer's disease have been followed by ten years of remarkable and increasing clinical insight into the natural progression of the disorder. The concept of a long, intermediary, prodromal phase between the first appearance of amyloid plaques and tangles and the manifestation of dementia is now well established. The major challenge for the next decade is to chart the many cellular processes that underlie this phase and link the biochemical alterations to the clinical manifestation of Alzheimer's disease. We discuss here how genetics, new cell culture systems, and improved animal models will fuel this work. We anticipate that the resulting novel insights will provide a basis for further drug development for this terrible disease.

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          Most cited references153

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          Neuropathological stageing of Alzheimer-related changes

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

            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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              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
                Annual Review of Neuroscience
                Annu. Rev. Neurosci.
                Annual Reviews
                0147-006X
                1545-4126
                July 08 2016
                July 08 2016
                : 39
                : 1
                : 57-79
                Affiliations
                [1 ]VIB Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, Leuven 3000, Belgium; email: ,
                [2 ]Center for Human Genetics, KU Leuven, Leuven 3000, Belgium
                [3 ]Leuven Research Institute for Neuroscience &amp; Disease (LIND), KU Leuven, Leuven 3000, Belgium
                [4 ]Institute of Neurology, University College London, WC1N 3BG London, United Kingdom
                Article
                10.1146/annurev-neuro-070815-014015
                27050320
                4bda7c26-fd92-4229-9c71-33fda1c3976b
                © 2016
                History

                Neurology,Health & Social care,Clinical Psychology & Psychiatry,Public health
                Neurology, Health & Social care, Clinical Psychology & Psychiatry, Public health

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