Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Disease

Abstract

<h3>Introduction</h3> Alzheimer's Disease (AD) is a neurodegenerative disease affecting millions of people worldwide, representing significant health and economic burdens. There has been a recent drive to develop more effective AD treatments. A potential strategy involves enhancing brain bioenergetics, or the metabolism of fuel molecules to create and use energy through glycolysis and oxidative phosphorylation (OxPhos). The regulation of mitochondrial turnover and function in the brain declines as we age, and it has become increasingly accepted that these metabolic alterations precede hallmark AD pathology, including amyloid-beta (Aβ) plaques and neurofibrillary tangles. An overlapping set of mechanisms involving redox dysregulation, oxidative stress, and mitochondrial dysfunction may be related to mild cognitive impairment (MCI) and AD. Nicotinamide adenine dinucleotide (NAD) has been identified as a promising molecular target for bioenergetic treatments as it is requisite for many redox reactions. The redox ratio (RR, i.e., NAD+/NADH) is a mark of the system's ability to carry out ATP synthesis. NAD+ levels decrease as we age, which compromises energy production in the mitochondria, impairs clearance of damaged mitochondria, and impacts our brain's capacity to react to oxidative stress. Since mitochondrial dysfunction and oxidative stress are believed to play a role in the pathophysiology of age-related diseases, boosting NAD levels could be an effective AD treatment. Nicotinamide Riboside (NR) is a naturally occurring, over the counter, commercially available, and safe vitamin B3-based NAD+ precursor supplement. Several lines of evidence suggest that NR is a mitochondrially-favored NAD+ precursor. Data supports the safety and efficacy of using NR to increase NAD+ levels in humans, but these studies have not measured the RR at critical tissue sites, such as the brain, to determine the therapeutic potential of oral NR supplementation. This study proposes a novel intervention strategy for patients with MCI or mild AD that targets redox dysregulation and oxidative stress in the brain using NR. Our primary objective is to validate the effect of NR supplementation on NAD+ levels and RR in the brain of patients with MCI or mild AD. Our secondary aim is to quantify the impact of NR supplementation on ensuing markers of mitochondrial function and oxidative stress in MCI and mild AD patients. Our third, exploratory aim, is to correlate neuroimaging measurements with clinical assessments. <h3>Methods</h3> A 12-week open-label, clinical trial of NR supported by the National Institute on Aging (R01AG066670, Du/Forester), we plan to enroll a total of 50 participants - 25 with MCI and 25 with mild AD, all with at least one copy of the APOE ε4 allele. Participants will be asked to take 1,000 mg NR daily over 12-weeks, and to come in for three scanning visits. We will use novel neuroimaging methods —spectroscopy on a 4T scanner to enable in vivo measurement of NAD+, NADH and RR, along with markers of mitochondrial function tied to NAD, including creatine kinase (CK), ATPase, and glutathione (GSH)—a molecule essential for cellular repair. Our primary outcome measures are NAD+ levels and RR. Our secondary outcome measures are CK/ATPase activity and GSH levels. Our exploratory outcome measures include the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for cognition and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) for daily functioning. <h3>Results</h3> Previous clinical trials of NR pharmacokinetics in humans support the safety and efficacy of using NR to increase NAD+ levels in the plasma. Emerging data also highlights important health benefits this supplement may have. We recently received preliminary spectroscopic data following a course of NR supplementation in healthy volunteers (N=4) which observed elevations in NAD+ and RR after two weeks. Only a small difference of downstream effects, CK/ATPase activity and GSH levels, were observed, which could be due to the short period of NR treatment. We hypothesize that oral NR will increase NAD+ and RR in the medial prefrontal cortex and will increase GSH levels and CK/ATPase activity in the brain. For our exploratory aim, we hypothesize that oral NR will improve cognitive status and functional abilities, as measured by the RBANS and ADCS-ADL. <h3>Conclusions</h3> We are investigating NR to target redox dysregulation and oxidative stress in the brain in those with MCI or mild AD. We aim to document and quantify the neurobiological and clinical effects of NR supplementation in MCI and mild AD using in vivo brain imaging. This novel intervention strategy of brain bioenergetics has thus far received minute empirical attention and may represent an alternative strategy for treating MCI and mild AD. Early detection and repair of neural dysfunction at this critical stage could significantly alter disease course and improve functional outcomes. <h3>This research was funded by</h3> National Institutes of Health