Potential Benefit of Nicotinamide Observed in Proof-Of-Concept Trial of Alzheimer Disease

Joshua D. Grill, PhD

In a phase 2a proof-of-concept trial, treatment with nicotinamide (Genentech) resulted in significantly less change on Clinical Dementia Rating-Sum of Boxes (CDR-SB) in patients with early Alzheimer disease (AD) relative to those on placebo. Above all, the benefits observed in the trial warrant further study for nicotinamide as a treatment for early AD, the study investigators wrote.¹

Presented at the 2023 Alzheimer’s Association International Conference (AAIC), held July 16-20, in Amsterdam, Netherlands, the trial featured 47 individuals who received either 1500 mg twice daily of nicotinamide or placebo, for a 12-month period. Results showed no significant treatment effects on secondary biomarker outcomes of cerebrospinal fluid (CSF) phospho-tau181, amyloid-ß (Aß)40, Aß42, and total tau (all P >.05); however, mean changes in CSF p-tau181 (0.4 [±29.8] vs 10.4 [±41.8]) and total tau (8.4 [±228.6] vs 60.5 [±237.5]) favored nicotinamide.

Previous research has shown that decline nicotinamide adenine dinucleotide (NAD+) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. The proof-of-concept trial, led by Joshua D. Grill, PhD, professor of neurobiology and behavior at the University of California, Irvine, included individuals aged 50 years and older with mild cognitive impairment or dementia because of AD, and who had a Mini-Mental State Examination score greater than 20. Patients entered the study on stable medications for at least 4 weeks, had CSF Aß42 levels less than or equal to 600 pg/mL or a ratio of total tau to Aß42 greater than 0.39.

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On the primary outcome of change in CSF p-tau231, no statistically significant difference was observed on ANCOVA models (mean difference, 2.06 [SE, 4.03]; P = .61); although, greater mean declines were found in the nicotinamide arm (–4.7 [±14.5]) than placebo (–2.3 [±10.6]). Nicotinamide was associated with significantly less change on CDR-SB (estimate, –1.42 [SE, 0.65]; P = .03) but not on cognitive or functional assessments, explained through the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (estimate, –1.93 [SE, 1.93]; P = .32) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living for Mild Cognitive Impairment scale (estimate, –3.10 [SE, 1.86]; P = .10).

Prior to treatment initiation, 1 patient dropped out and 6 dropped before completion, 2 in the nicotinamide arm and 4 in the placebo arm. The therapy continued to show a safe profile, with adverse events that were balanced throughout the trial, and few attributed to the treatment itself.

In 2020, a 10-week pilot trial using supplementation of nicotinamide riboside was found to be well tolerated in the blood of older adults with MCI, with treated patients demonstrating positive functional changes in brain and frailty measures. Changes in cognition, evaluated through the Montreal Cognitive Assessment, were not observed with nicotinamide riboside treatment.²

More recently, a published analysis of nicotinamide riboside supplementation showed an ability to augment NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. In the analysis, investigators studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659). Oral supplementation of the agent resulted in increased NAD+ levels in NEVs and decreased NEV levels of Aß42, pJNK, and pERK1/2.³

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REFERENCES
1. Grill JD, Tam S, Thai B, et al. A phase 2a proof-of-concept double-blind, randomized, placebo-controlled trial of nicotinamide in early Alzheimer’s disease. Presented at: AAIC 2023; June 16-20; Amsterdam, Netherlands. Abstract 77979
2. Orr ME, Kotlowski E, Bair-Kelps D, et al. Results from a pilot study: the effects of nicotinamide riboside on mild cognitive impairment. Alzheim & Dement. 2020;16(S9):e044746
3. Vreones M, Mustapic M, Moaddel R, et al. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging Cell. 2023;22(1):e13754. doi:10.1111/acel.13754.