PROJECT SUMMARY Polypharmacy is common among nursing home (NH) residents and is most prevalent among residents with Alzheimer's Disease and Related Dementias (ADRD) due to their high burden of multiple chronic conditions that predispose them to medication use. Polypharmacy is dangerous for NH residents with ADRD because it substantially increases the risk of drug interactions. Fall-related injuries, including fractures, joint dislocations, and hemorrhages, are one of the most common and impactful adverse outcomes of drug interactions and result in morbidity, disability, and death. Many theoretical interactions between drugs have been identified and healthcare providers believe that drug interactions are common and harmful among older NH residents with ADRD, yet limited data exist about which interactions are most clinically significant. Given that drug interactions resulting from polypharmacy are likely a major, yet modifiable, cause of fall-related injuries among older NH residents with ADRD, identifying drug interactions and their effects is essential for avoiding fall-related injuries. Thus, the overall objective of this proposal is to identify, test, and validate clinically significant drug interactions in NH residents with ADRD through a series of rigorous epidemiological studies that employ novel drug interaction screening and causal inference methods. The central hypothesis is that multiple clinically significant drug interactions will increase the risk of fall-related injuries, and that this risk will be greatest among individuals with the most severe cognitive impairment and on higher medication doses. This hypothesis will be tested through three specific aims: Aim 1 (Screening), Conduct hypothesis-free high-throughput semi-automated screening to identify potential interactions involving drug pairs and triads that increase the risk of fall-related injuries among NH residents with ADRD; Aim 2 (Testing), After prioritizing interaction screening results with the guidance of a multidisciplinary expert stakeholder panel, perform a series of hypothesis-driven studies to quantify the effects of drug interactions on fall-related injuries, including dose, duration, and NH resident subgroup effects; and Aim 3 (Replication), Conduct a series of validation studies in independent data to determine whether the drug interactions identified during screening and testing are consistently associated with fall-related injuries among NH residents with ADRD. To accomplish the three proposed aims, a large novel database of NH electronic health record information be leveraged along with national MDS 3.0 clinical assessment records linked to Medicare health insurance and prescription drug claims. The proposed research is highly significant because it will provide clinically actionable empirical evidence to help guide the prescribing, deprescribing, and management of medications to minimize the risk of important drug interactions and fall-related injuries among N...