PROJECT SUMMARY/ABSTRACT Reducing polypharmacy by discontinuing medications with reduced benefits and increased risks is a priority in older adults (OAs) with Alzheimer’s Disease and Related Dementias (ADRD). Low-dose aspirin for primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has been proposed as a target for discontinuation, with limited real-world data suggesting high variation in prescribing and discontinuation. Guidelines recommend against aspirin for primary prevention in OAs, while supporting its use for secondary prevention; however, applicability to OAs with ADRD is questionable. Reduced life expectancy for OAs with ADRD may translate into lower long-term ASCVD benefits, while increased potential for drug interactions may increase short-term bleeding risk. On the other hand, higher ASCVD risk among OAs with ADRD may position them for greater risk of ASCVD events previously observed in other populations in weeks after discontinuing aspirin, and the anti-inflammatory and anti-thrombotic effects of aspirin could also protect against further progression of cognitive or functional decline. The exclusion of OAs with ADRD from randomized trials of aspirin and limited availability of observational data on aspirin use (a non-prescription drug) leaves patients, providers, and caregivers with little evidence about benefits and harms to guide informed decisions about aspirin discontinuation. Our long-term goal is to improve decision-making, care quality, and outcomes for OAs with ADRD, through improved evidence and treatment guidelines about medications optimization as ADRD progresses. The proposed retrospective cohort study will use records on daily aspirin use uniquely available for a national cohort of Veterans Affairs (VA) nursing home (NH) residents with ADRD, linked to Minimum Data Set (MDS) assessments, electronic health records, and VA and Medicare utilization data over 2016-2023. Specific aims are to (1) Identify clinical and socio-environmental factors predicting aspirin discontinuation in OAs with ADRD after NH admission, stratified by ASCVD status; (2) Examine effects of discontinuing aspirin on ASCVD events, major bleeding, emergency department/hospital admissions, and mortality, stratified by ASCVD status; and (3) Examine effects of discontinuing aspirin on cognitive function, functional dependence, and behavioral/psychological symptoms of dementia. To focus our aims on generating robust, clinically- and policy-relevant evidence, we will use pharmacoepidemiologic methods to reduce selection bias and confounding. Aim 2 is a prevalent new-user study applying covariate balancing methods and competing risk models, with supplementary analyses to address time-varying aspirin exposure and confounders. Aim 3 will assess time-varying exposures and confounding using inverse-probability-weighted marginal structural models. This study will inform future practice guidelines to address if aspirin can be safely disco...