NAD+ Therapy for Improving Memory & Cerebrovasular Function in Patients with MCI

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PROJECT SUMMARY/ABSTRACT Amnestic mild cognitive impairment (aMCI) is the earliest symptomatic stage in the development of Alzheimer's disease (AD), which is among the fastest growing causes of morbidity and mortality in the Unites States. Elevated blood pressure and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) occurs with aging and is linked to the development of aMCI and AD, primarily through the transmission of damaging pressure waves to the cerebral vasculature, resulting in cerebrovascular dysfunction and neuronal damage. Risk factor modification through positive lifestyle behaviors such as healthy diet and regular aerobic exercise have, thus far, been the most effective strategies for improving cognitive function in patients with aMCI. In this regard, chronic calorie restriction (CR) prevents age-related vascular and cognitive dysfunction, in part by reducing large elastic artery stiffness and blood pressure; however, adherence to CR and other healthy lifestyle behaviors is poor among late middle-aged and older adults. The objective of the parent award (K01 AG054731) is to conduct a randomized, placebo-controlled clinical trial to study the efficacy of a novel NAD-boosting and CR-mimicking compound, nicotinamide riboside (NR), for improving memory in older adults with aMCI by reducing large elastic artery stiffness and blood pressure and increasing cerebral blood flow. Because of the older age of the target population, the parent clinical trial was temporarily placed on hold in March 2020 due to concerns surrounding the novel coronavirus disease (COVID-19) which disproportionately affects older adults. More recently, evidence has emerged linking SARS CoV2 infection (the virus that causes COVID-19) to a wide range of cardiovascular complications including vascular endothelial dysfunction, myocarditis, thrombosis, and ischemic stroke. Importantly, there is evidence of cardiovascular dysfunction even among individuals who did not develop the severe respiratory symptoms attributed COVID-19. Given the higher risk of COVID-19 among older adults and the potential for SARS CoV2 infection to impact the cardiovascular outcomes of the parent trial, there is an urgent need to implement additional protective measures to preserve the safety and integrity of the parent clinical trial. Accordingly, the purpose of this administrative supplement is to address COVID-19-related impact to the parent award by incorporating additional safety measures through the use of enhanced personal protective equipment (PPE), increasing staff to assist with virtual testing sessions, servicing key research equipment that was unused during the period in which the study was on hold, and adding the assessment of SARS CoV2 antibodies to all participants in the parent trial. These additional measures are necessary safely resume the parent clinical trial and protect the integrity of the data allowing us to continue to fulfill an important research objective of NIA by investigating promising interventions for ameliorating cognitive impairment in individuals with aMCI.