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      Alzheimer’s Disease: The Case for a Paradigm Shift

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      proceedings-article
      1
      ScienceOpen
      RExPO22
      2-3 September, 2022
      Alzheimer’s disease, proteinopathy, proteinopenia, loss-of-function, Aβ hypothesis
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            Abstract

            The widely accepted notion that the insoluble fraction of proteins, once in their cross-beta conformation (amyloid) at the end of the process of aggregation, drives neurodegeneration has been challenged by recent work. Data from a range of different experiments contradict the presumed neurotoxicity of aggregated protein. While the clinico-pathologic model that has defined neurodegenerative diseases for over a century has proven helpful for the development of symptomatic therapies, it has not yielded a single success in disease modification. Biomarker programs inspired in this model have yielded biomarkers of convergence, present in most but pathogenically irrelevant at the individual level. We will discuss opposing hypotheses around which neurodegeneration is classified and approached: gain- versus loss-of-function hypothesis. With evidence from biophysics and genetics, we propose that the loss of proteins in their soluble, monomeric state ( proteinopenia) is a more relevant causal factor than their presumed "toxic" accumulation in an amyloid state ( proteinopathy): proteins can only function when normal, and cease to function when abnormal. We outline a new approach to neurodegeneration with dual but complementary strategies for disease modification, namely rescue medicine (soluble protein replacement, a universal approach) as a precursor for future deployment of precision medicine (matching molecular interventions to biologically-suitable individuals, an individualized approach). The lessons are primarily drawn from Alzheimer's disease literature but the implications are extensive to other neurodegenerative disorders.

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            Author and article information

            Conference
            ScienceOpen
            26 August 2022
            Affiliations
            [1 ] James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
            Article
            10.14293/S2199-rexpo22007.v1
            7a769aeb-e01c-4054-bf1a-7d8b787b9fb3
            The Author

            Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

            RExPO22
            Maastricht, Netherlands
            2-3 September, 2022
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            ScienceOpen


            Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
            proteinopenia,Aβ hypothesis,loss-of-function,proteinopathy,Alzheimer’s disease

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