PROJECT SUMMARY Alzheimer's disease (AD) and related dementia (AD/ADRD) is a multifactorial and heterogeneous disorder. Most current studies focus on drug interventions for AD/ADRD and currently none of pharmacological intervention (PI) discovery research has been translated into effective treatments. However, increasing evidence demonstrates that non-pharmacological interventions (NPI), such as sleep, diet, dietary supplements, aerobic exercise, aromatherapy, light therapy, cognitive training, are potentially modifiable and thus offer alternative opportunities for AD/ADRD prevention. Thus, the objective of this project is to develop translational informatics approaches to aggregate, standardize and discover the effects of drug and NPI candidates on AD/ADRD using multi-modal data resources (i.e., biomedical literature, EHR, clinical trials) followed by animal model validation. To achieve our goal, we propose the following aims: 1) constructing a comprehensive Pharmacological And Non- Pharmacological Interventions for Alzheimer's Disease Knowledge Graph (PANIA-KG) from biomedical literature and other knowledge bases; 2) detecting, understanding, and visualization of drug repurposing signals of PIs, NPIs, and their synergistical effects for AD/ADRD using the PANIA-KG; 3) re-ranking and validating individual and synergistical drug repurposing signals using multimodal data sources and animal models. The successful completion of this project will deliver a comprehensive NPI knowledge graph, novel informatics approaches, ranked list of drug and NPI candidates, and validated synergistic intervention using multi-modal data sources. The generated approaches, PANIA-KG and ranked lists can further our clinical investigations and clinical trial design which focuses on synergistic effects of drug and NPIs for AD/ADRD.