Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold
{"title":"口服烟酰胺核苷（NR）补充剂对主观认知能力下降和轻度认知障碍的老年人的认知和阿尔茨海默病生物标志物的影响","authors":"Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold","doi":"10.1002/trc2.70023","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau<sup>217</sup>), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (<i>z</i>-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired <i>t</i>-tests were used for within-individual comparisons.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau<sup>217</sup> concentrations after taking NR, while an 18% increase with PBO (<i>p</i> = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau<sup>217</sup> concentrations significantly decreased during the NR phase compared to the PBO (<i>p</i> = 0.02), while step counts significantly increased during the NR phase than PBO (<i>p</i> = 0.04).</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Eight weeks NR supplementation is safe and lowered pTau<sup>217</sup> concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.</li>\n \n <li>NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.</li>\n \n <li>For between-group comparison, pTau<sup>217</sup> levels decreased with NR and increased with PBO at 8-week follow-up.</li>\n \n <li>For within-individual comparison, step counts increased after NR and decreased after PBO.</li>\n \n <li>A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733434/pdf/","citationCount":"0","resultStr":"{\"title\":\"Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment\",\"authors\":\"Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold\",\"doi\":\"10.1002/trc2.70023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau<sup>217</sup>), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (<i>z</i>-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired <i>t</i>-tests were used for within-individual comparisons.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau<sup>217</sup> concentrations after taking NR, while an 18% increase with PBO (<i>p</i> = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau<sup>217</sup> concentrations significantly decreased during the NR phase compared to the PBO (<i>p</i> = 0.02), while step counts significantly increased during the NR phase than PBO (<i>p</i> = 0.04).</p>\\n </section>\\n \\n <section>\\n \\n <h3> DISCUSSION</h3>\\n \\n <p>Eight weeks NR supplementation is safe and lowered pTau<sup>217</sup> concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.</li>\\n \\n <li>NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.</li>\\n \\n <li>For between-group comparison, pTau<sup>217</sup> levels decreased with NR and increased with PBO at 8-week follow-up.</li>\\n \\n <li>For within-individual comparison, step counts increased after NR and decreased after PBO.</li>\\n \\n <li>A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":53225,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"volume\":\"11 1\",\"pages\":\"\"},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2025-01-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733434/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70023\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/trc2.70023","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment
INTRODUCTION
Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.
METHODS
The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (z-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired t-tests were used for within-individual comparisons.
RESULTS
Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau217 concentrations after taking NR, while an 18% increase with PBO (p = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau217 concentrations significantly decreased during the NR phase compared to the PBO (p = 0.02), while step counts significantly increased during the NR phase than PBO (p = 0.04).
DISCUSSION
Eight weeks NR supplementation is safe and lowered pTau217 concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.
Highlights
The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.
NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.
For between-group comparison, pTau217 levels decreased with NR and increased with PBO at 8-week follow-up.
For within-individual comparison, step counts increased after NR and decreased after PBO.
A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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