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An updated Alzheimer’s disease progression model: incorporating non-linearity, beta regression, and a third-level random effect in NONMEM


Our objective was to expand our understanding of the predictors of Alzheimer’s disease (AD) progression to help design a clinical trial on a novel AD medication. We utilized the Coalition Against Major Diseases AD dataset consisting of control-arm data (both placebo and stable background AD medication) from 15 randomized double-blind clinical trials in mild-to-moderate AD patients (4,495 patients; July 2013). Our ADAS-cog longitudinal model incorporates a beta-regression with between-study, -subject, and -residual variability in NONMEM; it suggests that faster AD progression is associated with younger age and higher number of apolipoprotein E type 4 alleles (APOE*4), after accounting for baseline disease severity. APOE*4, in particular, seems to be implicated in the AD pathogenesis. In addition, patients who are already on stable background AD medications appear to have a faster progression relative to those who are not receiving AD medication. The current knowledge does not support a causality relationship between use of background AD medications and higher rate of disease progression, and the correlation is potentially due to confounding covariates. Although causality has not necessarily been demonstrated, this model can inform inclusion criteria and stratification, sample size, and trial duration.

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The authors would like to thank Dr. Mahesh Samtani (Johnson and Johnson Pharmaceutical Research and Development) for his technical guidance and invaluable input in conducting the analysis. The authors would also like to acknowledge CAMD database management team to provide the assembled dataset and to respond authors’ queries. All authors are employees of Pfizer Inc.

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Correspondence to Daniela J. Conrado.

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The Coalition Against Major Diseases: Data used in preparation of this article were obtained from the Coalition Against Major Diseases (CAMD) database ( A complete listing of CAMD members can be found at:

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Appendix: NONMEM 7.3 code for final model

Appendix: NONMEM 7.3 code for final model

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Conrado, D.J., Denney, W.S., Chen, D. et al. An updated Alzheimer’s disease progression model: incorporating non-linearity, beta regression, and a third-level random effect in NONMEM. J Pharmacokinet Pharmacodyn 41, 581–598 (2014).

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  • Alzheimer’s disease
  • Disease progression
  • Patient-level model-based meta-analysis
  • Coalition Against Major Diseases (CAMD)
  • ADAS-cog