Drug development for treating Alzheimer's disease (AD) has been challenging and expensive. Drug failures are very likely due, in large part, to the differential responses of patients to different treatments. Some subsets of patients have treatment moderators and respond differently. Identifying such responsive subsets has been challenging due to limited sample size in one clinical trial or may be beyond the scope of the ad-hoc analyses in individual clinical trials, considering the complexity of AD. Another important subset of patients are rapid progressors, who have faster rates of cognitive decline in a defined period and may respond differently to treatments than other AD patients. Predicting the rapid progressors and their differential responses is very challenging. Machine learning prediction has been no better than random guesses due to volatility of cognitive scores and insufficiency of comprehensive and fine-grained longitudinal clinical data. Pooling patient-level data from multiple clinical trials data may address the above challenges by increasing sample size and obtaining a better coverage/representation of the patient population. However, many clinical trials data are stored in distributed data access servers, and data use agreements often prohibit exporting the patient- level data out of the local servers. We aim to address the challenges via advanced informatics tools using AI/ML models. We will develop privacy-preserving federated models to harmonize local counterfactual effect estimation models into a global model without exchanging patient- level data. Aim 1 focuses on developing a federated subgrouping model based on differential responses. Aim 2 focuses on developing a federated counterfactual regression model using deep learning to predict rapid progressors and their differential responses. Aim 3 focuses on verifying and refining the subgroups prediction using real-world observation in nation-wide consortium data. If successful, this project will contribute to identifying patient subgroups that respond differently, which will result in smaller, less expensive, and more targeted AD clinical trials that expose fewer patients to experimental medications to which they are unlikely to respond.