Nicotinamide Adenine Dinucleotide Augmentation to Prevent or Reverse the Progression of Alzheimer's Disease in People with Down Syndrome

A large proportion of people with Down syndrome (DS) will exhibit Alzheimer's Disease (AD) neuropathology and will eventually develop dementia by age 60. The prevention and treatment of dementia is a high priority for people with DS and their families. Thus, there is an unmet need for strategies that can prevent, treat, or slow the progression of AD in people with DS. NAD+ depletion and dysregulation of NAD-dependent pathways are associated with increased tau phosphorylation and amyloid β accumulation, neuro-inflammation, dysregulated mitochondrial bioenergetics and neuro-degenerative changes in the brain similar to those observed in AD. In contrast to many AD drugs that target one mechanism, the NAD+ precursor, nicotinamide mononucleotide (NMN), targets AD neuropathology by multiple mechanisms: reducing the synthesis of oligomerized Aβ peptides and Aβ toxicity; increasing α-secretase activity; attenuating neuroinflammation; promoting neuronal regeneration; and improving mitochondrial energetics. Administration of oral NMN safely raises NAD+ levels in the blood and some other tissues in healthy adults. Thus, NMN is a promising candidate drug to prevent and treat AD but its safety, pharmacokinetics (PK), and pharmacodynamics (PD) have not been evaluated in people with DS. In accord with the reviewers' recommendation, we propose this multiple ascending dose, placebo-controlled, phase1 trial to determine the safety and tolerability, as well as PK and PD of NMN in adults with DS, as a first step towards evaluating its efficacy. The safety and tolerability will be assessed by structured monitoring of adverse events, safety laboratory tests, and electrocardiograms. The PK of oral, multiple ascending doses of NMN will be assessed starting with the 500 mg daily dose and escalating the dose in ascending order to the maximum dose of 1000 mg twice daily or a maximal tolerated dose. PK parameters (Caverage 0-24 h, Cmax, Tmax, z, AUClast, AUC24hr, AUCinf, and T1/2) will be computed using nonparametric methods. The PD will be assessed by analyzing blood NAD+ concentrations and circulating NAD+ metabolites (nicotinamide, 1- methylnicotinamide, N-Methyl-2-pyridone-5-carboxamide, N-Methyl-4-pyridone-3-carboxamide, nicotinic acid, and nicotinuric acid). We will determine whether oral NMN increases brain NAD+ levels, measured by ultra- high field 7T magnetic resonance spectroscopy (MRS). Exploratory outcomes include blood pressure and lipids that were improved in earlier human studies with NMN, muscle performance, and physical function. The trial is not long enough or large enough to evaluate effects on AD biomarkers or neuropsychological outcomes. The selection of a candidate drug that targets multiple AD mechanisms, innovative methods, rigorous trial design, and an inter-disciplinary team with substantial expertise in all content areas will facilitate accomplishment of the stated aims. The trial will provide important information on the safety, PK, and PD that is necessary for guiding the stepwise progression of this promising molecule towards larger efficacy trials.