MetroBiotech is developing a clinical stage NAD booster (MIB-626) for the treatment of patients with Alzheimer’s Disease (AD). The drug is a proprietary formulation of the crystalline form of b-Nicotinamide Mononucleotide (NMN), which has immunomodulatory and anti-inflammatory properties, and activates stress protective pathways that can be downregulated across many human diseases of aging. ADDF previously supported chronic preclinical toxicology studies with MIB-626 in which no adverse findings were observed.  Subsequently, a randomized control human trial (RCT) was initiated with oral MIB-626 tablets ingested by mild dementia AD participants. The objective of this trial was to determine whether MIB-626 or its metabolites dosed orally for 90 days, penetrates the blood brain barrier. The concentration of drug, and key metabolites thereof, are being measured in the CSF, blood and plasma, and determining NAD levels in brain using in vivo spectroscopy.  In our current grant application, we are requesting funding of a follow on a Phase 2b multi-center RCT with a 180-day dosing regimen.  This trial will determine whether MIB-626 improves CSF and plasma biomarkers of amyloid deposition, neuronal/axonal degeneration, synaptic function and neuroinflammation, as well as improvement of cognition and activities of daily living in trial participants.  Additionally, a better understanding of the oral bioavailability of NAD precursors and their metabolism in different tissues is necessary for their further development as therapeutics for AD.  Measuring the biochemical flux from NAD precursor to NAD biosynthesis and consumption will inform rational selection of the timing  and dose of MIB-626 to use in larger registration trials, and to ensure engagement of the hypothesized therapeutic mechanisms in AD.  Towards that end, we also include in this proposal a new phase 1 metabolism trial that will dose an isotopically labeled NMN as a tracer.