Testing whether the progression of Alzheimer’s disease changes with the year of publication, additional design, and geographical area: a modeling analysis of literature aggregate data

BACKGROUND: Our objectives were to develop a disease progression model for cognitive decline in Alzheimer’s disease (AD) and to determine whether disease progression of AD is related to the year of publication, add-on trial design, and geographical regions. METHODS: Placebo-controlled randomized AD clinical trials were systemically searched in public databases. Longitudinal placebo response (mean change from baseline in the cognitive subscale of the Alzheimer’s Disease Assessment Scale [ADAS-cog]) and the corresponding demographic information were extracted to establish a disease progression model. Covariate screening and subgroup analyses were performed to identify potential factors affecting the disease progression rate. RESULTS: A total of 134 publications (140 trials) were included in this model-based meta-analysis. The typical disease progression rate was 5.82 points per year. The baseline ADAS-cog score was included in the final model using an inverse U-type function. Age was found to be negatively correlated with disease progression rate. After correcting the baseline ADAS-cog score and the age effect, no significant difference in the disease progression rate was found between trials published before and after 2008 and between trials using an add-on design and those that did not use an add-on design. However, a significant difference was found among different trial regions. Trials in East Asian countries showed the slowest decline rate and the largest placebo effect. CONCLUSIONS: Our model successfully quantified AD disease progression by integrating baseline ADAS-cog score and age as important predictors. These factors and geographic location should be considered when optimizing future trial designs and conducting indirect comparisons of clinical outcomes.