Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Dementia - Alzheimer's Disease (AD) is the most prevalent neurodegenerative disease of aging, affecting ~5.4 million
individuals in the United States with a predicted increase to 13.8 million by 2050. This would be a substantial
burden on healthcare systems. Thus, developing new and effective treatment strategies is imperative. In this
vein, changes in metabolism and mitochondrial dysfunction have been identified as hallmarks of the aging
process. The brain consumes ~20% of the body's glucose, of which ~80% is metabolized in mitochondria to
generate ATP and support brain function. Mitochondrial dysfunction results in decreased ATP production and
release of free radicals with elevated oxidative stress during aging. Mitochondrial function is mediated, in part,
by nicotinamide adenine dinucleotide (NAD, including oxidizing and reducing forms, i.e. NAD+ and NADH).
Unfortunately, decreases in NAD+ levels, and consequently the redox ratio (NAD+/NADH), are associated with
normal aging, especially after age 45, and also with numerous diseases such as AD. Accumulating evidence
suggests that nicotinamide riboside (NR), an orally bioavailable precursor of NAD+, can enhance mitochondrial
function and help slow or reverse these age-related abnormalities. Currently, 30+ clinical trials, including two AD
studies, are registered on clinicaltrials.gov using NR and related compounds. However, no studies to date have
investigated in vivo metabolic and bioenergetic changes associated with NR supplementation because of the
challenges in measuring NAD+/NADH, namely low concentration (<1mM) and overlapping resonances with other
metabolites. Such measurement requires dedicated, state-of-the-art imaging approaches. To that end, we have
developed novel neuroimaging approaches to measure in vivo NAD+ and NADH, as well as other markers of
mitochondrial function, including creatine kinase (CK)/ATPase activity and the antioxidant glutathione (GSH)—
a molecule essential for cellular repair that has functional ties to NAD. These technical achievements undergird
our current proposal, which aims to investigate the neurobiological mechanisms and clinical effects of NR in
patients with mild cognitive impairment (MCI)/mild AD using in vivo neuroimaging techniques. We propose a 12-
week, open-label, proof of concept study to measure the effects of oral NR (1g/day) on brain energy metabolism,
oxidative stress, and cognitive functioning in MCI/mild AD patients. This study may provide crucial information
about NAD-related molecular mechanisms in MCI/AD, and facilitate the development and refinement of this
promising treatment approach. In summary, our innovative theoretical framework, driven by our pilot data and
published literature, includes three conceptual prongs: first, MCI/mild AD is associated with excessive redox
dysregulation, oxidative stress and deficient mitochondrial function; second, these abnormalities could be
remediated by NR; and third, the downstream effects of NR would accelerate CK/ATPase activities, thereby
increasing GSH levels and, in turn, improving cognitive function. Thus, identifying the precise molecular
mechanisms involved in MCI/AD-related bioenergetic dysfunction will provide important therapeutic targets.
