title: Computable cause-and-effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis.
abstract: BACKGROUND
  The discovery and development of new treatments for Alzheimer's disease (AD) requires a profound mechanistic understanding of the disease. Here, we propose a model-driven approach supporting the systematic identification of putative disease mechanisms.
  
  
  METHODS
  We have created a model for AD and a corresponding model for the normal physiology of neurons using biological expression language to systematically model causal and correlative relationships between biomolecules, pathways, and clinical readouts. Through model-model comparison we identify "chains of causal relationships" that lead to new insights into putative disease mechanisms.
  
  
  RESULTS
  Using differential analysis of our models we identified a new mechanism explaining the effect of amyloid-beta on apoptosis via both the neurotrophic tyrosine kinase receptor, type 2 and nerve growth factor receptor branches of the neurotrophin signaling pathway. We also provide the example of a model-guided interpretation of genetic variation data for a comorbidity analysis between AD and type 2 diabetes mellitus.
  
  
  CONCLUSIONS
  The two computable, literature-based models introduced here provide a powerful framework for the generation and validation of rational, testable hypotheses across disease areas.
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany; Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for IT, Bonn, Germany.
authors.forename: Alpha Tom
authors.initials: AT
authors.lastname: Kodamullil
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany.
authors.forename: Erfan
authors.initials: E
authors.lastname: Younesi
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany; Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for IT, Bonn, Germany.
authors.forename: Mufassra
authors.initials: M
authors.lastname: Naz
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany; Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for IT, Bonn, Germany.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bagewadi
authors.affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany; Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn-Aachen International Center for IT, Bonn, Germany. Electronic address: martin.hofmann-apitius@scai.fraunhofer.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann-Apitius
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000502:physiology / Q000503:physiopathology; D015897:Comorbidity; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor
keywords: APP; Alzheimer's disease; Alzheimer's disease model; Neurotrophin signaling; OpenBEL; Type 2 diabetes mellitus