Computable cause-and-effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis

Alzheimers Dement. 2015 Nov;11(11):1329-39. doi: 10.1016/j.jalz.2015.02.006. Epub 2015 Apr 4.


Introduction: 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.

Discussion: The two computable, literature-based models introduced here provide a powerful framework for the generation and validation of rational, testable hypotheses across disease areas.

Keywords: APP; Alzheimer's disease; Alzheimer's disease model; Neurotrophin signaling; OpenBEL; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / physiology
  • Brain / physiopathology
  • Comorbidity
  • Humans
  • Models, Neurological*
  • Neurons / physiology*
  • Polymorphism, Single Nucleotide


  • APP protein, human
  • Amyloid beta-Protein Precursor