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International Journal of Alzheimer’s Disease
Volume 2012, Article ID 978742, 9 pages
Research Article

A Unifying Hypothesis for Familial and Sporadic Alzheimer's Disease

1Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
2Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6
3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5

Received 25 July 2011; Revised 4 November 2011; Accepted 4 November 2011

Academic Editor: Lucilla Parnetti

Copyright © 2012 Carole J. Proctor and Douglas A. Gray. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Alzheimer's disease (AD) is characterised by the aggregation of two quite different proteins, namely, amyloid-beta (Aβ), which forms extracellular plaques, and tau, the main component of cytoplasmic neurofibrillary tangles. The amyloid hypothesis proposes that Aβ plaques precede tangle formation but there is still much controversy concerning the order of events and the linkage between Aβ and tau alterations is still unknown. Mathematical modelling has become an essential tool for generating and evaluating hypotheses involving complex systems. We have therefore used this approach to discover the most probable pathway linking Aβ and tau. The model supports a complex pathway linking Aβ and tau via GSK3β, p53, and oxidative stress. Importantly, the pathway contains a cycle with multiple points of entry. It is this property of the pathway which enables the model to be consistent with both the amyloid hypothesis for familial AD and a more complex pathway for sporadic forms.