Background: A mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Methods: The model was fit to the longitudinal ADAS-cog scores from 817 patients. Risk factors (age, apolipoprotein epsilon 4 [APOE epsilon 4] genotype, gentler, family history of AD, years of education) and baseline severity were tested as covariates. Results: Rate of disease progression increased with baseline severity. Age, APOE epsilon 4 genotype, and gender were identified as potential covariates influencing disease progression. The rate of disease progression in patients with mild to moderate AD was estimated as approximately 5.5 points/yr. Conclusions: A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE epsilon 4 genotype, and gender also influence the rate of disease progression. (C) 2011 The Alzheimer's Association. All rights reserved.