Nicotinamide Riboside for Alzheimer's Disease

Overseen By Brent Forester, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Mclean Hospital

Must not be taking: Benzodiazepines, Barbiturates, Opiates, others

Disqualifiers: Psychotic disorder, Stroke, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates how nicotinamide riboside, a form of Vitamin B3, might benefit individuals with mild cognitive issues or early Alzheimer's. The goal is to determine if this supplement can enhance brain energy, reduce brain stress, and improve memory and thinking skills. Participants will take the supplement daily for 12 weeks. Suitable candidates have mild memory problems or early Alzheimer's and are not currently taking high doses of niacin. As an Early Phase 1 trial, this research seeks to understand how the supplement functions in people, providing participants the opportunity to explore its potential benefits firsthand.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. If you are taking niacin (or a vitamin supplement with niacin) over 200mg, you must stop for two weeks before starting. Also, you cannot use medications that affect cognition or certain supplements like mitochondrial enhancers.

Is there any evidence suggesting that nicotinamide riboside is likely to be safe for humans?

Research has shown that nicotinamide riboside (NR) is generally safe for people. In a study with older adults experiencing mild memory problems, participants took NR and reported only minor side effects, such as stomach upset and headaches.

Another study examined NR's effects on sleep and thinking skills, finding no serious side effects, which suggests NR is safe for these groups.

NR is also present in some supplements, further indicating its general safety. However, since this study is in its early stages, it remains important to assess its safety and effectiveness for individuals with Alzheimer's and mild memory problems. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about nicotinamide riboside for Alzheimer's disease because it offers a novel approach compared to existing treatments like cholinesterase inhibitors and NMDA receptor antagonists. Unlike these standard options, which primarily aim to manage symptoms, nicotinamide riboside is a form of vitamin B3 that targets cellular energy production, potentially addressing the disease at a more fundamental level. This treatment could enhance brain cell resilience and repair, offering new hope for slowing down or altering the progression of Alzheimer's disease.

What evidence suggests that nicotinamide riboside might be an effective treatment for Alzheimer's?

Research has shown that nicotinamide riboside (NR) can increase levels of NAD+, a molecule that aids energy production in the brain. This rise in NAD+ might enhance brain function for some individuals. Studies suggest that NR reduces oxidative stress, a condition that can damage brain cells and may be linked to Alzheimer's disease. Additionally, NR has improved blood flow in the hippocampus, the brain region responsible for memory. Although improvements in memory have not yet been proven, these positive changes in brain health offer hope for individuals with mild cognitive impairment or mild Alzheimer's dementia. Participants in this trial will take NR to further explore its potential benefits for these conditions. ^{1 3 6 7 8}

Who Is on the Research Team?

Brent P Forester, MD

Principal Investigator

Mclean Hospital

Fei Du, PhD

Principal Investigator

Mclean Hospital

Are You a Good Fit for This Trial?

This trial is for individuals aged 55-89 with mild cognitive impairment or mild Alzheimer's dementia, who can understand study risks and consent. They must speak English fluently, have a study partner, carry the APOE ε4 allele or show positive AD biomarkers. Exclusions include serious medical conditions affecting cognition, recent mood disorders, psychotic history, MRI contraindications, NR intolerance, recent strokes or substance abuse.

Inclusion Criteria

Ability to speak and read fluently in English

My hearing and vision are normal or corrected to normal.

I understand the study's risks and goals, and I can sign the consent form.

Exclusion Criteria

I am currently taking supplements to boost my mitochondria or antioxidants.

I have taken L-DOPA, anti-Parkinsonian drugs, or anti-amyloid treatments.

MRI safety contraindications

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants take 4 pills daily, each containing 250 mg NR, for 12 weeks

12 weeks

Baseline, 6 and 12 weeks (in-person)

Follow-up

Participants are monitored for changes in mood, brain redox state, NAD+ levels, functional status, mitochondrial function, antioxidant levels, behavioral symptoms, spirituality, and cognitive status

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nicotinamide riboside

Trial Overview The trial tests whether Nicotinamide Riboside (NR) improves brain energy metabolism and reduces oxidative stress in patients with mild cognitive impairment or Alzheimer's dementia. It aims to see if NR can enhance cognitive function by supplementing the body's energy molecules.

How Is the Trial Designed?

Group I: Mild Cognitive Impairment and Alzheimer's Dementia Experimental Treatment 1 Intervention

Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.

Nicotinamide riboside is already approved in United States, European Union for the following indications:

Approved in United States as Niagen for:

• Dietary supplement for general health and wellness

Approved in European Union as Tru Niagen for:

• Dietary supplement for general health and wellness

Who Is Running the Clinical Trial?

Mclean Hospital

Lead Sponsor

Trials

221

Recruited

22,500+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Nicotinamide riboside (NR) is a promising NAD+ precursor that has shown potential health benefits in treating various conditions, including cardiovascular, neurodegenerative, and metabolic disorders, based on numerous animal and human studies.

Research indicates that NR may also have therapeutic applications against infections, such as SARS-CoV-2, but challenges related to its bioavailability and safety need to be addressed for effective translation into clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Mehmel, M., Jovanović, N., Spitz, U.[2021]

Nicotinamide riboside (NR) was safely administered to 20 older adults with mild cognitive impairment (MCI) over a 10-week period, resulting in a significant 2.6-fold increase in blood NAD+ levels without any adverse effects reported between the NR and placebo groups.

While NR treatment did not improve cognitive function as measured by the Montreal Cognitive Assessment (MoCA), it did lead to a reduction in cerebral blood flow in specific brain regions, indicating that further research is needed to explore its potential effects on cognition and brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. Orr, ME., Kotkowski, E., Ramirez, P., et al.[2023]

Long-term supplementation of nicotinamide riboside (NR) over 2 years in individuals with ataxia telangiectasia (A-T) was found to be safe and well tolerated, with most participants experiencing no adverse effects.

The study showed significant improvements in neuromotor function, particularly in coordination and eye movements, with a slower progression of symptoms compared to historical data, indicating potential therapeutic benefits of NR in managing A-T.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Presterud, R., Deng, WH., Wennerström, AB., et al.[2023]

Nicotinamide riboside, a precursor to NAD and a form of Vitamin B3, has been shown to enhance insulin sensitivity, promote mitochondrial biogenesis, and support brain health, particularly in models of Alzheimer's disease.

It is metabolized through two pathways, one that produces nicotinamide and another involving specific kinases that help raise NAD levels in tissues, suggesting its unique health benefits may be linked to these metabolic processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Chi, Y., Sauve, AA.[2021]

Nicotinamide-loaded solid lipid nanoparticles (SLNs) functionalized with phosphatidylserine (PS) showed improved brain delivery and safety, making them a promising option for treating Alzheimer's disease.

In a rat model, PS-functionalized SLNs significantly enhanced cognitive function and preserved neuronal cells better than traditional oral nicotinamide administration, indicating their potential effectiveness in early Alzheimer's treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer's disease animal model by reducing Tau hyperphosphorylation. Vakilinezhad, MA., Amini, A., Akbari Javar, H., et al.[2020]

Oral supplementation with nicotinamide riboside has shown potential in improving learning and memory while reducing Alzheimer's disease-related pathology in mouse models, indicating its efficacy in combating age-related cognitive decline.

Nicotinamide riboside is well tolerated in humans with minimal side effects, suggesting it could be a safe therapeutic option for enhancing cognitive function and maintaining brain health as we age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can nicotinamide riboside protect against cognitive impairment? Braidy, N., Liu, Y.[2021]

Nicotinamide riboside (NR), a form of vitamin B3, was found to be safe in various toxicity studies, including a 90-day rat study, with no genotoxic effects and no mortality at high doses (5000 mg/kg).

The lowest observed adverse effect level for NR was determined to be 1000 mg/kg/day, indicating that while it is generally safe, higher doses may lead to toxicity in organs such as the liver and kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of nicotinamide riboside, a form of vitamin B3. Conze, DB., Crespo-Barreto, J., Kruger, CL.[2019]

Nicotinamide ribose (NR) supplementation for 3 months improved cognitive functions, such as short-term spatial memory in aged mice and contextual fear memory in Alzheimer's disease (AD) model mice, indicating its potential efficacy in combating cognitive decline.

NR supplementation also reduced harmful effects associated with AD, such as the accumulation of amyloid-beta (Aβ) and the activation of astrocytes, suggesting a mechanism of action that may help prevent the progression of dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. Xie, X., Gao, Y., Zeng, M., et al.[2022]

In an 8-week clinical trial with overweight but healthy participants, nicotinamide riboside (NR) significantly increased whole blood NAD+ levels in a dose-dependent manner, with increases of 22%, 51%, and 142% for doses of 100, 300, and 1000 mg, respectively.

The study found NR to be safe, with no significant adverse effects reported compared to placebo, and it did not negatively impact cholesterol levels or 1-carbon metabolism, supporting its potential as a dietary supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Conze, D., Brenner, C., Kruger, CL.[2023]

Nicotinamide riboside (NR) is a form of vitamin B3 that effectively increases NAD+ levels, which may help counteract age-related declines in this important metabolite.

In a 90-day safety study on Sprague Dawley rats, NR-E showed no significant adverse effects at doses up to 1,200 mg/kg/d, establishing a no-observed-adverse-effect-level (NOAEL) of 500 mg/kg/d for males and 1,200 mg/kg/d for females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. Marinescu, AG., Chen, J., Holmes, HE., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10828186/

A randomized placebo-controlled trial of nicotinamide riboside ... Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03061474

Nicotinamide as an Early Alzheimer's Disease Treatment The purpose of this research study is to test whether nicotinamide, also known as vitamin B3 or niacinamide, taken in high doses, can reduce phosphorylation ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1064748122000641

Effects of Orally Administered Nicotinamide Riboside on ... This study proposes a novel intervention strategy for patients with MCI or mild AD that targets redox dysregulation and oxidative stress in the brain using NR.

4. neurologylive.com neurologylive.com/view/nicotinamide-riboside-shows-effects-hippocampal-features-not-improved-memory

Nicotinamide Riboside Shows Effects on Hippocampal ... New research reveals nicotinamide riboside supplementation enhances hippocampal perfusion in adults with mild cognitive impairment, but memory ...

5. alzres.biomedcentral.com alzres.biomedcentral.com/articles/10.1186/s13195-025-01693-y

Pharmacokinetic and pharmacodynamic assessment of oral ... The Nicotinamide as an Early AD Treatment (NEAT) study tested high-dose (1500 mg PO BID) oral nicotinamide in participants with Mild Cognitive ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05500170

Benefits of Nicotinamide Riboside Upon Cognition and Sleep This study proposes to examine the benefits of NR supplementation on sleep and cognitive function in older adults with comprehensive subjective and objective ...

7. alzdiscovery.org alzdiscovery.org/uploads/cognitive_vitality_media/Nicotinamide_Riboside_UPDATE.pdf

Nicotinamide Riboside Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer's Drug. Discovery Foundation (ADDF).

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11733434/

Cognitive and Alzheimer's disease biomarker effects of oral ... Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. Metab Brain Dis. 2019;34(1):353‐366. doi: 10.1007/s11011 ...