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

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Abstract

Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888

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Data Availability

The minimum datasets necessary to interpret, verify and extend the research in the article are available within the paper and its Supplementary Information. The trial was registered on ClinicalTrials.gov: NCT02942888.

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Acknowledgements

We would like to thank Beverly Orsak and Terry Romo for assisting with study coordination and patient visits, Rozmin Jiwani for assisting with study visits and Meghana Koleti for data entry; Crystal Franklin in the Research Imaging Institute staff for data curation and essential preprocessing steps. We also thank Dr. Brian Kennedy for offering valuable insights on experimental design.

Funding

Some authors were supported in part by funds from the National Institutes of Health (NIH South Texas Medical Scientist Training Program: T32GM113898, NIMH: R01MH074457-11S1, NIMH: R01MH074457, NCATS Translational Scientist Training Program: TL1TR002647-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. Miranda E. Orr, Nicolas Musi, and Becky Powers contributed equally to this study.

Authors and Affiliations

  1. Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, 575 Patterson Ave, Winston-Salem, NC, 27101, USA

    Miranda E. Orr

  2. Salisbury VA Medical Center, Salisbury, NC, 28144, USA

    Miranda E. Orr

  3. Research Imaging Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, USA

    Eithan Kotkowski & Peter T. Fox

  4. Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, USA

    Paulino Ramirez, Jonathan Gelfond & Bess Frost

  5. Department of Cell Systems and Anatomy, University of Texas Health Science Center San Antonio, San Antonio, TX, USA

    Paulino Ramirez & Bess Frost

  6. Geriatric Research, Education & Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA

    Darcy Bair-Kelps, Qianqian Liu, Jonathan Gelfond & Becky Powers

  7. Department of Diabetes & Cancer Metabolism, City of Hope, Duarte, CA, 91010, USA

    Charles Brenner

  8. Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Mark S. Schmidt

  9. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore, 138648, Republic of Singapore

    Anis Larbi, Crystal Tan & Glenn Wong

  10. Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Sara Espinoza & Nicolas Musi

  11. Department of Medicine, Division of Geriatrics, Gerontology, and Palliative Medicine, University of Texas Health Science Center San Antonio, San Antonio, USA

    Becky Powers

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Contributions

Research study design: MEO, PTF, NM, and BP; subject enrollment: DBK; conducted experiments: EK, DBK, MSS, YW, JG, and BP; provided reagents: CB; data analyses and interpretation: MEO, EK, PR, CB, PTF, JG, SE, BF, NM, and BP; drafted the manuscript: MEO, EK, and BP; critical revision: MEO, EK, CB, PTF, JG, SE, NM, and BP.

Corresponding author

Correspondence to Miranda E. Orr.

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Conflict of interest

ChromaDex Inc. provided the investigators with NR and placebo. Charles Brenner, a co-author, is an inventor of intellectual property on uses of nicotinamide riboside. He serves as Chief Scientific Advisor of ChromaDex and owns ChromaDex stock. Dr. Brenner’s contributions included data interpretation regarding NAD+ metabolites and manuscript editing. He was not involved in study design or execution. Dr. Orr reports a grant from US Department of Veterans Affairs during the conduct of the study. In addition, Dr. Orr has a patent biosignature and therapeutic approach for neuronal senescence pending outside the scope of this work. No other co-authors have COIs to declare.

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Orr, M.E., Kotkowski, E., Ramirez, P. et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. GeroScience 46, 665–682 (2024). https://doi.org/10.1007/s11357-023-00999-9

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