PROJECT SUMMARY/ABSTRACT Dementia is a major public health concern in older adults. Alzheimer’s disease (AD) accounts for 50% to 60% of dementia cases and nearly half of dementia-related deaths. Cholinesterase inhibitors (ChEIs) form the first line of pharmacotherapy for AD. However, the treatment effectiveness of ChEIs is considered modest and their use leads to adverse effects. Urinary incontinence is a prominent adverse effect of ChEI treatment, which is commonly implicated in prescribing cascade - a clinical phenomenon where the ChEI-induced urinary incontinence leads to prescribing of antimuscarinics. ChEIs and antimuscarinics interaction tends to nullify the modest treatment benefit of ChEIs and can worsen AD due to the therapeutically opposing mechanism of actions. This worsening of AD can precipitate additional cascades - prescribing of memantine for moderate-to- severe AD, and/or antipsychotics to manage behavioral symptoms of AD, and/or may lead to Serious Adverse Events (SAEs). Our preliminary analyses revealed that 6% of AD patients initiated antimuscarinics after ChEIs initiation, and memantine and antipsychotics were initiated by 30% and 23% AD patients, respectively, after the initial cascade. Although some studies have described the initial prescribing cascade of ChEIs in AD, none of the studies have evaluated the impact of prescribing cascades due to the drug-drug interaction of ChEIs and antimuscarinics. Therefore, the overall goal of this research is to evaluate the healthcare impact of the prescribing cascades of ChEIs and their associated interactions among community-dwelling older adults with AD. The specific aims of the proposed research are to: (1) examine the extent of prescribing cascades of ChEIs in older adults with AD; and (2) assess all-cause SAEs associated with ChEI-antimuscarinic interaction in older adults with AD. The study will involve propensity score-matched cohort design based on a national cohort of older adults > 65 years with AD. The initial prescribing cascade of ChEIs will include initiation of antimuscarinics. Further cascades will include initiation of memantine (for moderate-to-severe AD) and antipsychotics (for behavioral symptoms of AD). All-cause SAEs s will include all-cause hospitalization, emergency department visits, institutionalization, and mortality. Multi-year multistate Medicare data involving Parts A, B, and D will be used to test the following hypotheses: (i) ChEI-antimuscarinic drug-drug interaction leads to further cascades due to worsening of AD leading to prescribing of memantine for moderate-to-severe AD, as well as prescription of antipsychotics to manage behavioral symptoms of AD, and (ii) there is a greater risk for all-cause SAEs due to ChEI-antimuscarinic interaction. Concomitant ChEI-antimuscarinic users will be compared with concomitant users of ChEIs and mirabegron, a non-anticholinergic alternative. The study will adjust for selection bias within the multivariable context ...