Preservation of brain NAD+ as a novel non-amyloid based therapeutic strategy for Alzheimer’s disease

Tragically, there is currently a lack of effective medicines to prevent, treat, or reverse AD, and the problem is growing exponentially as our population rapidly ages. A large part of the failure to develop effective medicines for patients with AD is due to the disproportionate amount of resources that have been devoted to pursuing

putative therapeutic targets linked to the largely unsuccessful amyloid hypothesis of AD. Only very recently has the first anti-amyloid based therapy been conditionally approved, and many major medical centers are declining to offer this to patients due to serious concerns regarding its safety and efficacy. Thus, it is imperative that we

discover and develop new and complementary therapeutic targets for AD. Aging is well known to be the greatest risk factor for AD, and it has been demonstrated that brain nicotinamide adenine dinucleotide (NAD+) levels decrease in people as they age, and even more so in AD. NAD+ is a critical cofactor and energy metabolite in

brain health and function, and we hypothesize that preserving brain NAD+ will prevent, treat, and potentially even reverse AD-like pathology and behavioral deficits in a preclinical mouse model of AD, known as 5xFAD mice. Importantly, we have also shown that this mouse model of AD is characterized by significantly diminished levels

of brain NAD+ as well, thereby modeling this important aspect of human AD. We are testing our hypothesis with a novel small molecule compound (P7C3-A20) that crosses the blood-brain barrier (BBB) and potently and selectively stimulates activity of nicotinamide adenine monophosphate ribosyltransferase (NAMPT). NAMPT is

the rate limiting enzyme in NAD+ synthesis, and peripherally-administered P7C3-A20 elevates brain NAD+ levels under conditions of disease or injury that would otherwise deplete NAD+. The protective effect of P7C3-A20 to preserve NAD+ and thereby block nerve cell degeneration has been demonstrated in multiple preclinical models,

including mouse models of TBI, Parkinson’s disease, and stroke, as well as a monkey model of hippocampal nerve cell death. Extended daily administration of P7C3-A20 upwards of a year has shown no toxicity or side effects in any animal system, including monkeys in which extensive pathological analysis across all organ

systems was conducted after 9 months of daily oral ingestion. Three early pathophysiologic features of AD that are dependent on NAD+ availability in the brain are axonal degeneration, BBB deterioration, and excessively high death of young hippocampal neurons that arise from adult hippocampal neurogenesis. We propose that

augmenting NAD+ levels in the AD brain will provide a novel means of preventing, treating, and potentially even reversing AD. We will thus test whether treatment with P7C3-A20 will be effective in early-disease (treatment from 2-6 months of age), mid-disease (treatment from 6-12 months of age), and late-disease (treatment from 12-

18 months of age) in both male and female 5xFAD mice. Protective effects in these domains will also be correlated with objective measure of cognitive and neuropsychiatric behavioral function, as well as other classical pathologic features of AD, including neuroinflammation, tau pathology, and amyloid plaque accumulation. We

predict that P7C3-A20 will preserve brain NAD+ levels and protect axonal structure, BBB integrity, and hippocampal neurogenesis at each of these disease stages, which will be associated with generally improved cognitive and behavioral function, as well as reduced damage in the brain. If so, then our results will establish

robust proof of principle for a novel approach to preventing, treating, and possibly reversing AD by preserving normal NAD+ levels in the brain. Importantly, our results could also establish a basis for future clinical trials with a compound currently in drug development (P7C3-A20), together with a plasma biomarker of brain nerve cell

degeneration (acetylated-tau) that we have previously established in both mice and humans.