Vitamin B Alters the Risk and Severity of Alzheimer’s Disease

Highlights

·        Diet interventions to improve nicotinamide adenine dinucleotide levels (NAD+) reduce neurodegeneration in flies modeling Alzheimer’s disease.
·        Alzheimer’s flies with mutations suppressing an enzyme that consumes NAD+ also reduces neurodegeneration.
·        Vitamin B, which contains the NAD+ precursor nicotinamide, is associated with a lower incidence and severity of Alzheimer’s disease in data from people in the UK Biobank.

Given all the talk in the media about Alzheimer’s disease, it’s not too surprising that this neurodegenerative disease is the most common cause of dementia and that it doesn’t have a cure. With exorbitant amounts of money and hours spent on failing to make a drug for Alzheimer’s, wouldn’t it be ironic (and perhaps poetic) if the way to prevent this neurodegeneration was found in a readily available vitamin or supplement? 

Published in Cell Death & Disease, Yu and colleagues from the University of Cambridge show that dietary supplementation of nicotinamide, a precursor to a molecule critical to metabolic health and aging called nicotinamide adenine dinucleotide (NAD+), suppressed neurodegeneration in the fly model of Alzheimer’s disease. Then, using data from a huge data repository called the UK Biobank, the British research team showed that these effects carried over to humans. People who took vitamin B — which includes nicotinamide — were at a lower risk for Alzheimer’s.

“Our results highlight … the potential for NAD+-based therapies,” said Yu and colleagues in regards to treating Alzheimer’s.

What’s the link between Alzheimer’s, mitochondria, and NAD+?

Mitochondria are the cells’ powerhouses. They produce adenosine triphosphate (ATP), the cell’s energy currency. Mitochondrial dysfunction has serious consequences for animal tissues with high energetic demands, such as the brain and muscle. The prevailing consensus is that, in Alzheimer’s disease, mitochondrial impairment is secondary to toxic molecular-initiating events.

NAD+ serves hundreds of critical biological functions, but none are more notorious than its role in energy formation in the mitochondria. The inhibition of major NAD+-consuming enzymes — such as a family called the PARPs — or the dietary supplementation of its precursor increases NAD+ levels, protects against mitochondrial dysfunction. So, does boosting NAD+, either by administration of precursors or suppression of NAD+ consuming enzymes, protect against Alzheimer’s disease?

Neurodegeneration in Alzheimer’s flies is linked to NAD+ levels

For these reasons, Yu and colleagues explored the mitochondrial and metabolic consequences of introducing the toxic protein that causes Alzheimer’s — human amyloid-β (Aβ) peptide — into the brain of flies. It turns out that these insects are a powerful model for studying how this disease is caused and unfolds; they’re also helpful for identifying novel preventive strategies for this disease.

The University of Cambridge researchers show that flies modeling Alzheimer’s disease have major mitochondrial dysfunction in the brain and decreased levels of NAD+. But they were able to reverse the neurodegeneration by modulating NAD+ levels in several ways in these Alzheimer’s flies.

First, Yu and colleagues showed that the dietary supplementation of an NAD+ precursor vitamin, nicotinamide (or vitamin B3), recovered the NAD+ levels that had been altered in flies modeling Alzheimer’s. What’s more, the addition of nicotinamide improved mitochondrial function and prevented neurodegeneration in these flies. 

Next, the University of Cambridge researchers looked to see if these results could be replicated by evaluating Alzheimer’s flies with mutations that suppress the NAD+ consuming enzyme PARP. The Alzheimer’s flies with suppressed PARP recovered their NAD+ levels to that of flies without Alzheimer’s. And like the Alzheimer’s flies supplemented with nicotinamide, PARP suppression prevented neurodegeneration and promoted survival in flies modeling Alzheimer’s disease.

In humans, vitamin B alters the risk and severity of Alzheimer’s. 

But do these fly results translate to humans? To answer this question, Yu and colleagues turned to data from the UK Biobank, a biomedical database and research resource containing health records of more than half a million British individuals. From this data, the University of Cambridge researchers found that participants taking vitamin B, which contains nicotinamide (vitamin B3), have a lower risk and severity of Alzheimer’s disease. They propose that these results support the potential of NAD+-based therapies to prevent Alzheimer’s disease.

“Taken together, our results show a protective trend for vitamin B against Alzheimer’s disease as well as a decrease in a characteristic of Alzheimer’s disease, sleepiness, in participants who take vitamin B,” said the University of Cambridge researchers. “The strengthening of these associations in the subset of participants with a higher genetic risk reinforce the protective trend for vitamin B.”

The PARP conundrum

Although suppression of the NAD+ consuming enzyme PARP in Alzheimer’s flies reduced neurodegeneration, whether this would carry over to humans is unclear. In this paper, the UK Biobank data does not show that PARP1 mutations decrease the odds for Alzheimer’s; in fact, it increases the risk of the neurodegenerative disease. However, it is unclear what these mutations are doing in humans, whether they are suppressing or activating PARP1, since the mutations are unknown.

Nevertheless, the role of PARP1 is to protect against DNA damage. The reason PARP inhibitors are used to treat cancer is that several forms of cancer are more dependent on PARPs than regular cells; without PARPs, the genomes of the cancer cells get so unstable that the cells die. So, whether taking PARP inhibitors would actually constitute a long term solution to prevent Alzheimer’s potentially could backfire by causing the buildup of more mutations. 

Can boosting NAD+ really alter the risk of Alzheimer’s?

Yu and colleagues propose that the salvage pathway is particularly attractive since boosting the availability of NAD+ precursors can delay aging and a wide range of diseases. Based on the protective effect of nicotinamide in a mouse model of Alzheimer’s disease, a phase two clinical trial on using nicotinamide as an early Alzheimer’s disease treatment is already underway (NCT03061474).

There is a heap of research showing the safety and effectiveness of NMN, the metabolic intermediate between nicotinamide and NAD+, in promoting longevity and treating or preventing age-related diseases in mice, and there is growing evidence that these effects could translate into people. Over the past year, clinical trials have shown the safety and effectiveness of NMN in humans: one on prediabetes in postmenopausal women and another on muscle performance in men in their sixties and older. So, since nicotinamide gets converted to NMN, it’s possible that the administration of NMN also suppresses neurodegeneration.