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PLoS One. 2018 Jan 29;13(1):e0190615. doi: 10.1371/journal.pone.0190615. eCollection 2018.

The development of a stochastic mathematical model of Alzheimer's disease to help improve the design of clinical trials of potential treatments.

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Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, London, United Kingdom.
Janssen Prevention Center, Leiden, The Netherlands.


Alzheimer's disease (AD) is a neurodegenerative disorder characterised by a slow progressive deterioration of cognitive capacity. Drugs are urgently needed for the treatment of AD and unfortunately almost all clinical trials of AD drug candidates have failed or been discontinued to date. Mathematical, computational and statistical tools can be employed in the construction of clinical trial simulators to assist in the improvement of trial design and enhance the chances of success of potential new therapies. Based on the analysis of a set of clinical data provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI) we developed a simple stochastic mathematical model to simulate the development and progression of Alzheimer's in a longitudinal cohort study. We show how this modelling framework could be used to assess the effect and the chances of success of hypothetical treatments that are administered at different stages and delay disease development. We demonstrate that the detection of the true efficacy of an AD treatment can be very challenging, even if the treatment is highly effective. An important reason behind the inability to detect signals of efficacy in a clinical trial in this therapy area could be the high between- and within-individual variability in the measurement of diagnostic markers and endpoints, which consequently results in the misdiagnosis of an individual's disease state.

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