Abstract
OBJECTIVE: Identification of clinically meaningful subphenotypes of disease progression can enhance the understanding of disease heterogeneity and underlying pathophysiology. In this study, we propose a machine learning framework to identify subphenotypes of Alzheimer's disease progression based on longitudinal real-world patient records. METHODS: The framework, dynaPhenoM, extracts coherent clinical topics across patient visits and employs a time-aware latent class analysis to characterize subphenotypes. We validated dynaPhenoM using three patient databases with a total of 3952 AD patients across the United States, demonstrating its effectiveness in revealing mild cognitive impairment (MCI) progression to AD. RESULTS: Our study identified five subphenotypes associated with distinct organ systems for disease progression from MCI to AD, including common subtypes across cohorts-respiratory, musculoskeletal, cardiovascular, and endocrine/metabolic-as well as a cohort-specific digestive subtype. CONCLUSION: Our study unravels the complexity and heterogeneity of the progression from MCI to AD. These findings highlight disease progression heterogeneity and can inform both diagnostic and therapeutic strategies, thereby advancing precision medicine for Alzheimer's disease.