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

Trial Summary

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.

What data supports the effectiveness of the drug Nicotinamide Riboside for Alzheimer's Disease?

Research shows that Nicotinamide Riboside (NR) can increase levels of NAD+ in the body, which is important for energy metabolism and brain function. In studies with mice, NR improved memory and reduced Alzheimer's-related brain changes. Additionally, a small human study found NR to be safe and increased NAD+ levels, suggesting potential benefits for brain health. ^{1 2 3 4 5}

Is nicotinamide riboside safe for human use?

Nicotinamide riboside (NR), a form of vitamin B3, has been studied for safety in both animals and humans. In human trials, NR was generally well-tolerated with no significant adverse effects reported, even at higher doses. Animal studies also showed no severe toxicity, although some effects on organs were noted at very high doses. ^{2 6 7 8 9}

How is the treatment nicotinamide riboside unique for Alzheimer's disease?

Nicotinamide riboside is unique because it is a form of Vitamin B3 that boosts levels of NAD+ (a molecule important for energy and cell health), which may help protect against age-related cognitive decline, unlike traditional Alzheimer's treatments that often focus on symptom management. ^{1 6 7 9 10}

What is the purpose of this trial?

This trial is testing nicotinamide riboside (NR), a form of vitamin B3, to see if it can help people with early memory problems or mild Alzheimer's. The idea is that NR can boost a molecule called NAD+ in the brain, which helps cells produce energy and reduces stress. Researchers hope this will improve brain function in these patients. Nicotinamide riboside (NR) is a precursor to NAD+ and has shown potential in improving learning and memory in animal models of dementia.

Research Team

Brent P Forester, MD

Principal Investigator

Mclean Hospital

Fei Du, PhD

Principal Investigator

Mclean Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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-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]

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]

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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Can nicotinamide riboside protect against cognitive impairment? [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer's disease animal model by reducing Tau hyperphosphorylation. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Safety assessment of nicotinamide riboside, a form of vitamin B3. [2019]

7. England 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. [2023]

8. United States 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. [2021]