Phase 2 Clinical Study Adds to Promising Research
TL;DR: Early research has been suggesting for a decade that nicotinamide riboside had the potential to improve cellular function in Alzheimer's disease. Now we have our first human clinical study, and it is consistent with the pre-clinical tests. Larger human studies are sure to follow.
Nicotinamide riboside has been a preferred NAD precursor for research in neurodegenerative diseases because if NAD metabolism is a problem, the niacin (NA) biosynthetic pathway is not well-expressed in nerve cells, and the nicotinamide (NAM) biosynthetic pathway can be downregulated due to stress and age.
Therefore, because the nicotinamide riboside (NR) pathway is active in neurons and skips a rate-limiting step for NAM, NR may be able to more effectively replenish intracellular NAD in neurodegenerative diseases than other NAD precursors. NMN can be expected to work similarly to NR, because NMN must be turned into NR before it can enter cells.
As early as 2013, research showed that NAD precursors could restore cognition in a mouse model of Alzheimer's by supporting mitochondria. They tested nicotinamide riboside (NR):
...Our studies suggest that dietary treatment with NR might benefit Alzheimer's disease cognitive function and synaptic plasticity, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.
By 2018, more evidence pointed to cellular energy and DNA repair as a contributing cause to Alzheimer's disease, and suggested that nicotinamide riboside (NR) normalized cerebral energy metabolism. The researchers concluded that NAD depletion played a "pivotal role" Alzheimer's, and that bolstering NAD+ levels in neurons had therapeutic potential for Alzheimer's disease.
Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease...NR-treated [Alzheimer's model] mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity...Our findings suggest a pivotal role for cellular NAD+ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD+ levels therefore have therapeutic potential for AD.
In 2020, the plot thickened a bit, when researchers realized not only that the gut microbiome might play a role in Alzheimer's, but also that the effect of nicotinamide riboside on the gut microbiome itself after oral supplementation might be a part of NR's therapeutic functions in Alzheimer's disease:
Alzheimer’s disease (AD) is the most common neurodegenerative disease. Growing evidence suggests an important role for gut dysbiosis and gut microbiota-host interactions in aging and neurodegeneration...In this study, we investigated the relationship between gut microbiota and NR treatment in APP/PS1 transgenic (AD) mice...Our results indicate an interplay between NR and host-microbiota in APP/PS1 mice, suggesting that the effect of NR on gut dysbiosis may be an important component in its therapeutic functions in AD.
In 2021, researchers were increasingly excited about the potential of NAD in neurodegenerative diseases, including Alzheimer's, but the early results were just with mice, and so next we had to wait for human tests.
Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer’s disease (AD)...Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients’ phenotypes.
Human Clinical Alzheimers Test Results
But now in 2023 we finally have our first test results back with humans, and they are promising. On January 26, 2023, researchers published the result of a Phase 2 clinical trial using a "combined metabolic activator" that included 1,000 mg of nicotinamide riboside.
The researchers followed 40 patients for 84 days -- 29 patients in the test group, and 11 in the placebo group. They found significant improvement in cognitive function in the test group compared to the placebo group, and these improvements corresponded with measurable physical changes, too, in hippocampal volume, cortical thickness, and metabolic plasma analysis.
We designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMAs improves cognitive functions in AD patients...We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.
This is a very promising result indeed, but there are two caveats.
First, it's only a Phase 2 study -- forty participants is not THAT many, so the statistical analysis, while sound, still requires follow-up with larger groups. Don't take my word for it; that's what the researchers themselves said: "Our results should be interpreted with caution until being confirmed by a randomized, double-blinded and placebo-controlled phase 3 clinical trial."
Second, because the test involved a combination of four different ingredients -- L-serine, Nicotinamide Riboside, NAC, and L-carnitine -- we can't know the relative contributions of each of the ingredients, or, indeed, whether they only work when combined.
Stay tuned for additional larger human tests. No one knows how those will come out, but as you can see from the trajectory of the research reviewed above, there is a reasonable chance that nicotinamide riboside will prove to be an important part of the solution.