Comparison and aggregation of event sequences across ten cohorts to describe the consensus biomarker evolution in Alzheimer's disease

Background: Previous models of Alzheimer’s disease (AD) progression were primarily hypothetical or based on data originating from single cohort studies. However, cohort datasets are subject to specific inclusion and exclusion criteria that influence the signals observed in their collected data. Furthermore, each study measures only a subset of AD-relevant variables. To gain a comprehensive understanding of AD progression, the heterogeneity and robustness of estimated progression patterns must be understood, and complementary information contained in cohort datasets be leveraged. Methods: We compared ten event-based models that we fit to ten independent AD cohort datasets. Additionally, we designed and applied a novel rank aggregation algorithm that combines partially overlapping, individual event sequences into a meta-sequence containing the complementary information from each cohort. Results: We observed overall consistency across the ten event-based model sequences (average pairwise Kendall’s tau correlation coefficient of 0.69 ± 0.28), despite variance in the positioning of mainly imaging variables. The changes described in the aggregated meta-sequence are broadly consistent with the current understanding of AD progression, starting with cerebrospinal fluid amyloid beta, followed by tauopathy, memory impairment, FDG-PET, and ultimately brain deterioration and impairment of visual memory. Conclusion: Overall, the event-based models demonstrated similar and robust disease cascades across independent AD cohorts. Aggregation of data-driven results can combine complementary strengths and information of patient-level datasets. Accordingly, the derived meta-sequence draws a more complete picture of AD pathology compared to models relying on single cohorts.