Research Summary Epidemiological data have indicated that the use of products with cannabidiol (CBD) and other cannabinoids have increased dramatically among adults over the age of 65. Recent survey data collected in Colorado indicate that older adults who use cannabinoids believe that it helps alleviate pain, helps improve sleep quality, and decreases negative affect (i.e., depression, anxiety). Older adults may also be taking cannabinoids like CBD because they believe it might have a positive impact on the progression of dementia and cognitive decline, as popularized by a recent Discover magazine article. Given the aforementioned socioeconomic trends, the preclinical data suggesting that CBD may be neuroprotective, and our preliminary data suggesting that CBD impacts key biomarkers of inflammation and oxidative stress, it is clearly time to assess the impact of these products on the cognitive health of older adults who are at high risk for AD. The significance of this question is underscored by both the rapidly aging population in the U.S. (>60 million adults over the age of 65 by 2025), the prevalence of MCI (~15–20%) and Alzheimer’s (about 10% or 6-7 million), as well as the enormous mortality, morbidity, and socioeconomic costs of AD. The proposed research will address this public health research need with a gold standard, 24 week, randomized, double-blind, placebo-controlled clinical trial (RCT) comparing full spectrum hemp-derived CBD, to CBD alone, and to placebo. The proposed study will determine whether CBD impacts the progression of biomarkers related to neurodegeneration and Alzheimer’s disease and determine whether CBD impacts measures of anxiety, depression, sleep, and pain in a population at high risk for AD. The research will also determine whether any effects of CBD on outcomes are mediated by the effect of CBD on biomarkers of inflammation and oxidative stress and/or changes in endocannabinoids. Given the number of older adults at risk for AD who are using CBD products and given that these individuals believe that these products are helpful, the proposed well-controlled trial will have a significant impact by informing the public about the effects of CBD, regardless of the outcome of the analyses (positive or negative).