Modeling Alzheimer’s disease progression using the disease system analysis approach

A novel mechanistic model based on a disease system analysis paradigm was developed to explore the role of homeostatic mechanisms involved in Alzheimer's disease (AD) progression. We used longitudinal AD Assessment Scale‐cognitive subscale (ADAS‐cog) scores from 926 subjects with AD on stable acetylcholinesterase inhibitor therapy randomized to placebo treatment in two 54‐week clinical trials. Alternative mechanistic models were evaluated by assuming that the rate of change of ADAS‐cog over time was jointly regulated by a process characterizing the deterioration of ADAS‐cog and by a process associated with a compensatory regulatory response. The model based on a time‐varying deterioration rate of ADAS‐cog performed better than the model based on a time‐varying homeostatic control. The covariate analysis indicated that baseline Mini‐Mental State Examination score, education, age, and apolipoprotein ε4 genotype had a significant effect on the level and shape of the trajectories of the mean model predicted ADAS‐cog change from baseline.

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