# A Proof of Concept Trial of a Sirtuin-NAD+ Activator in Alzheimer's Disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $873,053

## Abstract

Summary
In preclinical models, the upregulation of the sirtuin-NAD+ pathway by increasing intracellular NAD+ through
administration of NAD precursors, such as β nicotinamide mononucleotide (βNMN), engages the mechanisms
of aging and prevents or attenuates Alzheimer's disease (AD) pathology. In contrast to many AD drugs in
development that target one mechanism, NAD precursors may prevent AD pathology by multiple mechanisms:
by improving mitochondrial energetics; inducing a switch to non-amyloidogenic processing of amyloid
precursor protein (APP) due to increased α-secretase activity; preventing microglia-dependent Aβ toxicity;
attenuating neuroinflammation; promoting neuronal regeneration; and improving insulin action. NAD-
precursors are sold over the counter, and despite widespread claims of their benefits and growing use of NAD
precursors, carefully controlled studies of their pharmacology, efficacy, and safety have been limited.
In response to the Reviewers' recommendations, we have extensively revised the study and now propose a
smaller, single-site, 90-day randomized, placebo-controlled, parallel group, double-blind, trial in 24 participants
with mild AD dementia to demonstrate: 1) CNS penetration across the blood-brain barrier; and 2) the ability of
oral NMN to increase brain levels of NAD, using an innovative ultra-high field 7T magnetic resonance
spectroscopy (MRS) method. To determine whether βNMN penetrates the blood-brain barrier in humans, we
will measure the cerebrospinal fluid (CSF) concentrations of βNMN and its key metabolites at baseline and on
day 90 (Aim 1). We will assess whether βNMN engages the target mechanism by measuring the abundance of
NAD+ (a SIRT1 substrate) in the brain using ultra-high field 7T MRS and in peripheral blood mononuclear cells
using a validated LC-MS/MS assay (Aim 2). We will determine the effects of βNMN on circulating biomarkers
of aging that the geroscience experts have recommended (HbA1C, IGF1, T3, IL6, TNFα, and urinary F2-
isoprostane) (Aim 3). This trial is neither long enough nor large enough to determine the effects of βNMN on
clinical outcomes and AD biomarkers. However, we have included CSF and serum biomarkers of AD as well
as measures of global cognition, instrumental activities of daily living, and neuropsychiatric symptoms as
exploratory outcomes to estimate design parameters such as bias and precision of changes in outcomes, and
pre-post correlation to guide the design of subsequent efficacy trials.
The scientific rigor and innovation in the proposed proof-of-principle trial is underscored by the use of a high
quality crystalline formulation of βNMN; a dose-regimen informed by carefully performed pharmacokinetic
studies; rigorous sample collection procedures to ensure preanalytical stability; and evaluating the engagement
of the sirtuin-NAD+ pathway in the brain using ultra-high field 7T MRS. The trial will provide important
information on the engagement of target mechanisms that is nece...

## Key facts

- **NIH application ID:** 10457489
- **Project number:** 5R01AG071074-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** SHALENDER BHASIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $873,053
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457489

## Citation

> US National Institutes of Health, RePORTER application 10457489, A Proof of Concept Trial of a Sirtuin-NAD+ Activator in Alzheimer's Disease (5R01AG071074-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10457489. Licensed CC0.

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