A naturally occurring dietary supplement called nicotinamide riboside (NR) can enter the brain and have a therapeutic effect on the organ, according to a new study published in the journal Aging Cell. The research marks the first time it has been determined that NR can enter the brain. 


Christopher Martens, assistant professor of kinesiology and applied physiology at the Delaware Center for Cognitive Aging Research, and Dr Dimitrios Kapogiannis, a senior investigator at the National Institute on Aging, made this discovery. 


What happens after nicotinamide riboside is consumed?


When NR is consumed, it is readily converted into nicotinamide adenine dinucleotide (NAD+) inside the body. This chemical helps in repairing cells and damaged DNA. 


In a statement released by the University of Delaware, Martens said NAD+ is gradually lost as people get older or develop chronic diseases. He explained that the loss of NAD+ is linked to obesity and other negative lifestyle habits like smoking. 


Martens, who has been studying NR  since he was a postdoctoral fellow at the University of Colorado Boulder, found in an initial study that levels of NAD+ could be boosted in the blood if people ingested NR. However, at that time, it was not clear if NR could reach other tissues in the body. 


Martens said the study showed some preliminary signs of efficacy, including lower blood pressure in people who had high blood pressure initially, but until now, it was unknown whether NR reached targeted organs like the brain to have a real therapeutic effect. 


The researchers measured NAD+ levels in extracellular vesicles in blood


It is difficult to measure the level of NAD+ in the brain in humans. While there are emerging techniques involving magnetic resonance imaging (MRI), these only provide an indirect measure and are costly and difficult to perform. Instead of using techniques involving MRI, the team of researchers measured NAD+ directly in tiny particles called extracellular vesicles that originated from neurons and ended up in the blood. 


According to the study, the extracellular vesicles can provide cutting-edge blood-based biomarkers for brain disorders and serve as a "liquid biopsy" of neurons. The researchers got a rare look at what is inside the vesicles. 


The researchers selected vesicles with markers characteristic of neurons


Martens said each vesicle has a unique molecular signature on its surface, including proteins that give one clues about its origin. In the study, the researchers selected vesicles that carry markers that are characteristic of neurons, and so, they had confidence that the NAD+ measured in them reflects what happens in the neurons, and by extension, the brain. 


The researchers, using samples from their first initial clinical trial, determined that NAD+ levels went up in these vesicles after six weeks.


NAD+ resulted in changes in biomarkers of neurodegenerative disease


Martens said when NAD+ goes up in these vesicles, one can see an association with some of the biomarkers of neurodegenerative disease.  He explained that in people where the researchers saw an increase in NAD+, they also saw changes in biomarkers like amyloid beta and tau. These are both related to Alzheimer's disease. 


The researchers also found a correlation between these neurodegenerative biomarkers and change in NAD+. 


Martens said if NAD+ went up a lot, there was typically a larger change in some of the disease biomarkers. This explains that NAD+ is not only getting into the brain but is probably also having some effect on its metabolism and multiple interrelated pathways.  


Significance of the study


By studying these blood-based biomarkers, researchers could determine if NAD+ depletion is a cause of Alzheimer's and other neurodegenerative diseases. With more scientific advancements, these types of tests could become more accessible to the population for more routine testing. 


Currently, Martens is leading a study involving NR in older adults with mild cognitive impairment. Through the study, he aims to determine if an increased consumption of NR has an even larger effect in people with cognitive impairment.


Martens said people with cognitive deficits are more likely to have an accumulation of some of these biomarkers in the brain. 


Most of the drugs commercially available for the treatment of Alzheimer's disease only have a modest effect on the symptoms but do not significantly stop the underlying progression of the neurodegenerative disease. 


Martens said that in the ongoing trial, the researchers are measuring markers of cognitive function and other things related to functional independence and quality of life, but are also hoping to gain some insight on the underlying disease process. He also said that the researchers are hoping that the people who take NR might have preserved function.


After proving the efficacy of NR, Martens and Kapogiannis will test whether the increased use of NR improves cognition, and where it can be used to slow the progression of neurodegenerative disease.


Next, the researchers will try to determine if NAD+ increases in other tissues as well, and see if this could help resolve different diseases.