PROJECT SUMMARY/ABSTRACT Both the American Geriatrics Society and the Center for Medicare and Medicaid Services have identified anticholinergics as inappropriate medications in older adults due to their adverse cognitive effects causing an increased risk of Alzheimer's disease and related dementias (ADRD). Every year, as many as 30% of older Americans use at least one of these medications, and more than 50% use at least one strong anticholinergic in five years. Despite awareness of these adverse cognitive effects, there has been no decline in prevalence over the last two decades. Several studies have identified higher risks of ADRD among users of these medications, however it is unknown whether stopping these medications in current users results in acute and sustained improvements in cognition. We propose a new trial called “Reducing Risk of Dementia through De-prescribing (R2D2)” to determine the efficacy of a pharmacist-driven de-prescribing protocol to improve cognition among primary care older adults currently using an anticholinergic medication. We will focus the intervention on primary care patients at high risk of cognitive decline due to current cognitive complaints or those making at least one error on a cognitive screening tool, while excluding those with dementia. The design will be a cluster randomized trial, randomizing physicians to minimize risk of contamination. Participants will be randomized to usual care (UC) or an active intervention group (ACT) that will receive a pharmacist-based de-prescribing intervention modeled after our prior work. The R2D2 study will enroll 344 older adults to determine the impact of the intervention on cognition at 6, 12, 18, and 24 months after baseline. The trial will monitor the safety of the intervention on depression, anxiety, pain, insomnia, and quality of life. We hypothesize that the ACT group will have better scores on cognitive assessments, no change in safety measures, and improvement in quality of life scores compared to usual care. If our hypothesis holds, this study would prove that the adverse cognitive effects of anticholinergics are reversible in older adults at high risk of ADRD, providing support for further work testing time to cognitive decline or dementia as a primary outcome. Interventions delaying the onset of cognitive impairment and dementia will have a significant impact on both the quality and costs of care of the aging population.