PROJECT SUMMARY This application is in response to NOT-AG-22-025, Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease (AD). Mild cognitive impairment (MCI), characterized by reductions in episodic memory, executive function, and other domains of fluid cognitive function beyond what is expected with normal aging, predisposes individuals to age-related neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementias. Individuals with chronic kidney disease (CKD) are at high risk of MCI, with a prevalence approximately 2x the age-matched general population. The risk for MCI in CKD is in part mediated by large elastic artery (i.e. aortic) stiffness and increased systolic blood pressure (SBP), contributing to reductions in cerebral vascular function (e.g., increased pulsatile blood flow and reduced cerebrovascular reactivity, in part due to vascular oxidative stress), which precedes the clinical onset of dementia. Lowering SBP with conventional pharmacotherapy decreases risk for MCI and dementia; however, the vast majority of patients with CKD fail to achieve adequate BP control. Boosting NAD+ bioavailability in mouse models of aging and AD improves risk factors for cognitive impairment. In a pilot study, we found that boosting NAD+ via oral supplementation with nicotinamide riboside reduced SBP and aortic stiffness in midlife and older adults, suggesting that nicotinamide riboside supplementation improves multiple risk factors for mild cognitive impairment and AD. However, the efficacy and underlying mechanisms of nicotinamide riboside for improving brain health in adults with CKD, who are at high risk or MCI/dementia, are unknown but has been identified as high-priority research topics. Leveraging our funded parent award clinical trial, we propose to assess the efficacy of oral nicotinamide riboside to enhance brain health in adults with stage 3-4 CKD by adding measures of cognitive performance and cerebrovascular function. To assess mechanisms of action, we also will use participant serum to determine if the benefits of nicotinamide riboside supplementation are mediated by changes in circulating metabolites that reduce mitochondrial ROS production in cerebrovascular endothelial cells (CECs). Therefore, we are proposing to expand our parent award trial to include these clinical and mechanistic markers of brain health in this high-risk population. This research is highly relevant to AD and related dementias because it will evaluate a novel dietary supplement for improving cognitive function and established MCI/AD risk factors in adults with stage 3-4 CKD. Leveraging an ongoing trial will stimulate research in the AD field by allowing us to rapidly collect and disseminate results on the efficacy of dietary supplementation with nicotinamide riboside for decreasing the risk for mild cognitive impairment, AD and related dementias in a clinically-relevant, at-risk group. Thus, this ...