# Developing a NAMPT activator for Alzheimer’s disease

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $2,376,637

## Abstract

Currently there are no therapies that can slow or reverse the cognitive decline seen in late-onset Alzheimer's
disease (LOAD). The single greatest risk factor for this condition is chronological age and as the global population
ages, the number of AD cases is expected to continue to rapidly increase. This age-dependent association has
led many to suggest that strategies that slow or reverse aspects of brain aging might be of particular use in
patients with LOAD. In normal human subjects, there is an age-dependent decline in brain NAD+ levels and in
animal models, a decline in brain NAD+ is strongly associated with aging and cognitive decline, while restoring
NAD+ can improve cognitive function. Moreover, evidence suggests that in pre-clinical AD models, there is an
accelerated loss of NAD+ and that neurons are particularly vulnerable to a reduction in intracellular NAD+ levels.
It is well established that the rate limiting enzyme in the NAD salvage pathway is nicotinamide
phosphoribosyltransferase (NAMPT) and that the enzymatic activity of NAMPT largely determines the level of
NAD+ within cells. Here, we describe an early stage drug development proposal to advance a brain penetrant,
small molecule that augments NAMPT activity, thus increasing neuronal NAD+ levels and combating brain aging.
We describe the development plan of this molecule up to the IND filing stage. The ultimate clinical indication for
such a molecule would be in patients with LOAD and mild cognitive impairment. We have assembled a team
with extensive drug development and AD experience, both in the pre-clinical and clinical arena. This proposal
describes a series of milestones and go/no go decision points to advance our current set of three distinct
chemical series, all of which directly bind to NAMPT and increase enzymatic activity, to a single final clinical
candidate that would be ready to advance to Phase I testing in human subjects. This compound would be a first-
in-class small molecule that seeks to reverse the age-dependent decline in NAD+ levels as a means to treat mild
cognitive impairment in LOAD patients.

## Key facts

- **NIH application ID:** 10929451
- **Project number:** 5U01AG079828-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Beibei Chen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,376,637
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929451

## Citation

> US National Institutes of Health, RePORTER application 10929451, Developing a NAMPT activator for Alzheimer’s disease (5U01AG079828-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10929451. Licensed CC0.

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