Age-related cognitive decline has emerged as one of the major public health challenges of our time. It is well known that normal cognitive function requires an adequate blood supply to support neuronal activity. In the healthy young brain, cerebral blood flow is rapidly adjusted to meet the increased oxygen and nutrient demands of active brain regions via a homeostatic mechanism known as neurovascular coupling (NVC, or functional hyperemia). Preclinical and clinical studies demonstrate that NVC is impaired in normal aging, and experimentally induced impairment of NVC responses in young animals results in cognitive impairment. Restoration of NVC in these animals by targeted pharmacological treatments improves cognitive function. Testing specific interventions in humans that have demonstrated efficacy in animal models is a reasonable and prudent approach that may improve impaired NVC and may be the key to developing effective therapies to reverse or prevent age-related cognitive decline and Alzheimer’s Disease/ Alzheimer’s Disease related dementias (AD/ADRD) in older adults. Endothelial dysfunction and impairment of NVC responses have been associated with increases in the production of reactive oxygen species (ROS) that are one of the well-defined ‘Hallmarks of Aging’. Nicotinamide Adenine Dinucleotide (NAD) is one of the major regulators of ROS and has been shown to attenuate ROS production. Our preliminary studies indicate that NAD levels are profoundly reduced in brain vascular endothelial cells of aged mice and that restoration of NAD levels in normal aged mice (equivalent of ≥60 years of age in humans) using an NAD precursor rescues age-related endothelial dysfunction, restores NVC responses and attenuates cognitive decline. Age-related NAD depletion, endothelial dysfunction, and impaired NVC responses are observed in older adults even in the absence of predisposing vascular pathology. Although supplementation with the NAD precursor, nicotinamide riboside (NR), has been reported to increase blood cell NAD levels in humans, effects on endothelial function and NVC responses have not been investigated. Addressing this scientific gap is essential to further develop our understanding of the etiology of NVC impairment and establish its role in the genesis of cognitive decline in aging and AD/ADRD. Our central hypothesis is that restoration of NAD levels with NR in older adults will improve NVC responses and micro- and macrovascular endothelial function. This hypothesis will be tested by assessing the effects of treatment with oral NR (1g/day per os for 8 weeks) or placebo (8 weeks) in community dwelling older adults (60-85 years of age) in a randomized, double-blinded, placebo-controlled, parallel study design. These studies will determine whether NR supplementation alleviates endothelial and neurovascular dysfunction and, potentially, cognitive decline. We anticipate that identifying NAD dysregulation during aging as a driver of vascular dysfunctio...