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

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.

Keywords: Dementia; Geroscience; Mild cognitive impairment; NAD; Nicotinamide riboside; Placebo-controlled trial.

Fig. 1

Study design and timeline. The primary objective of the study was to assess safety and tolerability of NR in older adults with MCI. The primary outcome was change in cognition as measured by MoCA. CBC, complete blood count; ADLs, activities of daily living; IADLs, instrumental activities of daily living; MoCA, Montreal Cognitive Assessment; GDS, Geriatric Depression Scale; GAS, Geriatric Anxiety Scale; EXIT, executive interview; TAPS, test of auditory processing skills; CLOX, executive clock drawing task; MRI, magnetic resonance imaging; NR, nicotinamide riboside. Shaded cells indicate procedures were conducted during the study visit. Dose escalation strategy: 250 mg × 1 week, 500 mg × 1 week, 750 mg × 1 week, and 1 g to end of study (6 weeks)

Fig. 2

Study flow diagram. Of the 150 screened individuals, we present data from the 20 individuals that completed the study

Fig. 3

Oral supplementation with NR alters NAD+ blood metabolism. a Whole blood levels of NAD+ and associated metabolites from placebo- and NR-treated subjects before and after treatment. The pre-/post-difference relative baselines were estimated using the paired t-test and 95% confidence intervals, and the between-group differences were evaluated with the Welch t-test. b Diagram of NAD+ metabolism depicting analytes that significantly changed during the study. Data are plotted as within subject pre- vs post-levels. Open circles, baseline levels; gray circles, post-treatment values. Lines connect individual subjects. n = 10/group. *p < 0.05; **p < 0.01; ***p < 0.001. NR, nicotinamide riboside; NaM, nicotinamide; NA, nicotinic acid; NAR, nicotinic acid riboside; NAMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide; NAAD, nicotinic acid adenine dinucleotide; NAD+, nicotinamide adenine dinucleotide; ADPR, ADP-ribose; AMP, adenosine monophosphate; Me-4-Py, N-methyl-4-pyridone-5-carboxamide

Fig. 4

Effects of NR treatment in specific regions of the default mode network (DMN) and hippocampus reported as uncorrected p-values. a Medial prefrontal cortex (m. PFC), ventral anterior cingulate cortex (v. ACC), left mid frontal gyrus (l. MFG), left hippocampus (l. HC), right hippocampus (r. HC), left inferior parietal lobe (l. IPL), right inferior parietal lobe (r. IPL), posterior cingulate cortex (PCC), left mid temporal gyrus (l. MTG), and right mid temporal gyrus (r. MTG). b The change in precuneus cerebral blood flow (CBF) significantly, inversely correlated with post-treatment blood NAD+ levels. N=19 subjects; one subject was excluded due to poor image quality on post-visit. p = 0.0448; R² = 0.22. Change in CBF reflects normalized signal intensity values from MRI scans

Fig. 5

Effects of NR on DNA methylation profiles in peripheral blood mononuclear cells. a Cumulative distribution function plots showing methylation profiles of the most variable CpG sites in the range of 0.4–0.7 methylation frequency. b CpG volcano plots of differences between the placebo and NR intervention. X-axis, log2 fold-change of methylation value; Y-axis, −log10 of unadjusted p-values. Red horizontal line, p-value = 1 × 10⁻⁶. c Estimation plot of rate of aging using AgeAccelPheno (above) and paired mean difference (below) shows treatment-associated differences in rate of epigenetic aging between study arms. Dot, average paired mean difference; black vertical line, 95% CI; and distribution in placebo and NR groups