Unraveling the heterogeneity in Alzheimer's disease progression across multiple cohorts and the implications for data-driven disease modeling

Introduction Given study-specific inclusion and exclusion criteria, Alzheimer's disease (AD) cohort studies effectively sample from different statistical distributions. This heterogeneity can propagate into cohort-specific signals and subsequently bias data-driven investigations of disease progression patterns. Methods We built multi-state models for six independent AD cohort datasets to statistically compare disease progression patterns across them. Additionally, we propose a novel method for clustering cohorts with regard to their progression signals. Results We identified significant differences in progression patterns across cohorts. Models trained on cohort data learned cohort-specific effects that bias their estimations. We demonstrated how six cohorts relate to each other regarding their disease progression. Discussion Heterogeneity in cohort datasets impedes the reproducibility of data-driven results and validation of progression models generated on single cohorts. To ensure robust scientific insights, it is advisable to externally validate results in independent cohort datasets. The proposed clustering assesses the comparability of cohorts in an unbiased, data-driven manner.