In 2020, nearly six million people were living with Alzheimer’s disease in the US, and that number will likely increase in the coming decades. Attempts to develop drugs to treat the neurodegenerative condition have seen limited success, with only six drugs currently approved by the FDA. Researchers have also explored the potential of existing drugs to improve the condition of people suffering from this form of dementia. Niacin, a form of vitamin B3 also known as nicotinic acid, has recently caught the attention of some researchers in the field.
The vitamin has sparked interest over the past 20 years with a few epidemiological studies that reported an association between niacin intake and a reduction in risk of general cognitive decline. More recently, researchers have begun exploring whether the compound has a positive effect on individuals with neurodegenerative diseases. Research findings published in the last few years have suggested that niacin can modulate the activity of microglia, important immune cells in the brain, in mice models for Parkinson’s, glioblastoma, and multiple sclerosis. Initial evidence of this protective effect has now been shown in a mouse model for Alzheimer’s disease.
Based on the new data of niacin limiting Alzheimer’s progression in mice “and the fact that it is FDA approved, I believe it is worth a clinical trial in individuals with” mild cognitive impairment and early Alzheimer’s disease, University of Florida neuroscientist Malú Tansey, who is not involved in any of these niacin studies, writes in an email to The Scientist. Currently, clinical trials testing niacin for other neurodegenerative diseases are already underway, and at least one for Alzheimer’s treatment is awaiting grant approval.
Niacin and Alzheimer’s—the first hints of a link
Niacin is an essential nutrient obtained from foods, such as fish, beef, chicken, and whole grains, and supplement sources. The vitamin, in its pharmacological form, is prescribed to increase high-density lipoprotein (HDL) cholesterol, although its intake is not associated with a reduced risk of death, heart attack, or stroke.
A deficiency in niacin can cause pellagra, a condition that results in dementia (among other consequences). Since the 1980s, researchers have explored whether dietary niacin could help stave off some neurodegenerative diseases. A study conducted between 1993 and 2002 in a cohort of older adults in Chicago, for example, calculated niacin intake from dietary data on the participants’ food and supplement consumption. The team found that intake from both sources together was inversely associated with development of Alzheimer’s, and intake from food sources was also negatively associated with cognitive decline. A study published in 2017 also found a beneficial relationship between dietary intake of niacin in young adulthood and better cognitive function later in life.
These findings might not have been “particularly persuasive,” says Indiana University School of Medicine Alzheimer’s researcher Gary Landreth. But the existence of a potential link was “provocative,” he says. When Miguel Moutinho joined Landreth’s lab in 2016, the two decided to interrogate that link and see if it existed beyond the realm of epidemiological observation.
Aside from the epidemiological link between niacin, cognitive function, and Alzheimer’s, there was another piece of evidence that caught Moutinho’s eye. He says he was interested in how the so-called ketogenic diet has been associated with treatment or prevention of Alzheimer’s and other neurodegenerative diseases. One of the things this diet does, he adds, is increase the production of ketone bodies—molecules produced by the liver from fatty acids during periods of caloric restriction—which bind to the G-protein-coupled receptor HCAR2 (also known as GPR109A), for which niacin has high affinity.
Based on these two lines of evidence, says Moutinho, he started wondering where this niacin receptor was expressed in the brain. Together with Landreth and colleagues, he first explored the question in a mouse model of amyloid pathology—the accumulation of amyloid-β plaques, which is a hallmark of Alzheimer’s disease. They found that Hcar2, the gene that codes for HCAR2, was expressed significantly higher in the hippocampus and cortex of affected mice compared to mice from a control strain. When looking into postmortem brain tissue of humans, the authors also found the expression of the receptor to be much higher in samples from Alzheimer’s patients, compared to those not diagnosed with dementia.
The expression of the receptor was specifically associated with microglia: when these immune cells were depleted, the mRNA levels of Hcar2 declined significantly, while the expression was restored when microglia were repopulated. Moreover, Hcar2 expression increased in microglia surrounding amyloid-β plaques compared to those uninvolved with them. The gene’s activity seemed to play a beneficial role in how microglia interact with the amyloid plaques—mice lacking Hcar2 showed higher plaque burden in their brain tissue and increased neuronal loss.
These results answered Moutinho and colleagues’ question: in the brain, the HCAR2 receptor is mainly expressed in the microglia, and more specifically, in those individuals with Alzheimer’s disease.
Niacin might stimulate protective microglial activity
Microglia are one class of macrophages inhabiting the brain. They are constantly monitoring their environment, ready to protect neurons from microbial or parasitic infections. These immune cells, however, do not seem to have a specific program to target amyloid plaques in the context of Alzheimer’s. “There was never any directing of the evolutionary process for microglia to have either benefit or be detrimental in Alzheimer’s disease,” says David Morgan, a neuroscientist at Michigan State University and a paid speaker for the biotechnology company Biogen, which is working on therapies for Alzheimer’s. He was not involved in the niacin research.
Microglia, thus, likely have “a very mixed response to signals” coming from amyloid aggregation and other features of the disease, he says—many of these responses might help to ward off parasitic infections, but in the context of neurodegenerative diseases, some could be beneficial while others detrimental. Indeed, research shows that microglia’s phagocytic activity towards amyloid-β aggregates can be protective, but if these cells are overactive, they secrete inflammatory factors that can injure neurons and worsen the pathogenesis of Alzheimer’s disease.
Because Moutinho and colleagues found that microglial protective activities are stimulated by the HCAR2 receptor, and as niacin is known to bind to it, they tested whether a daily dose of the FDA-approved oral formulation of niacin, Niaspan, for 30 days could alter the development of the disease in their mouse model. The team reports that mice undergoing this treatment showed improved working memory, reduced plaque formation, and diminished neuronal loss, compared to those treated with a control solution without Niaspan.
As expected, Niaspan did not achieve this improvement in mice lacking the HCAR2 receptor. In the brain, HCAR2 is almost exclusively found in the microglia of animals with Alzheimer’s, making it “almost like a natural targeting” as only those cells will be sensitive to the therapy, says Moutinho.
While Morgan acknowledges that the authors “have pretty convincing data that they are really slowing the phenotype” by the activation of microglia achieved with the Niaspan treatment, he notes that they are not really treating Alzheimer’s, but rather “amyloid deposition,” which is not the only feature of the disease. The reason he brings this up, he adds, is that there are some manipulations of the microglia his team has performed “that benefit amyloid pathology but [worsen] tau pathology”—another feature of the disease related to the harmful aggregation of different proteins.
Nonetheless, as the authors also quantified the expression of Alzheimer’s relevant genes in treated and untreated mice, Morgan says that the pattern of activation they report is the one “you would like to see in a drug that could be useful for Alzheimer’s.” For instance, “they did not see increases in the proteins that we would call proinflammatory”—assumed to be involved in tau pathology—in those receiving Niaspan, he notes. Yet, when planning to treat people with Alzheimer’s disease, “you need to be very confident . . . that you don’t clear out the amyloid but exacerbate the tau pathology,” he adds. Morgan notes that further studies should assess the effect of Niaspan on tau proteins—something also acknowledged by the authors in their paper.
Clinical prospects for niacin use in Alzheimer’s and other neurodegenerative diseases
University of Calgary neuroimmunologist Wee Yong, who did not participate in this study but peer-reviewed it, says that this is a “very important work” as “the Alzheimer’s field has struggled for some time” trying to find ways to remove amyloid-β plaques. Niaspan’s effect on Alzheimer’s disease “needs to be tested in humans, of course, but this is . . . ripe for clinical translation,” he says.
This is the first time that a link between niacin and Alzheimer’s disease has been demonstrated in lab experiments. And recent studies by other teams, including Yong’s, have reported similar effects of niacin in other neurological disorders. In 2020, Yong and his colleagues showed that niacin could enhance the phagocytic activity of microglia, specifically its ability to remove myelin debris in cultured cells and in a mouse model of multiple sclerosis. “Treatment with niacin could rejuvenate . . . microglia to remove myelin debris and therefore to lead to improved myelin repair,” says Yong. This protective effect was also mediated by the HCAR2 receptor.
Yong says his team came upon niacin by screening a library of more than one thousand generic medications, while looking for an agent that could stimulate myelin repair. According to Yong, he and his colleagues are trying to initiate a clinical trial to test niacin treatment for multiple sclerosis, but first they “need to be more confident of the laboratory results.”
Yong and his collaborators have also reported that mice affected by glioblastoma—a type of cancer arising in the central nervous system—exhibited slower tumor growth and survived longer when treated with niacin. The compound stimulates microglia and other immune cells to engulf and kill tumor cells. Based on these findings, a clinical trial of niacin treatment for glioblastoma patients is currently taking place at the University of Calgary.
Research on Parkinson’s disease has also revealed a potential role for niacin. Treatment with this vitamin has proven to reduce neuroinflammation in these patients, and analyses of their blood samples suggests that HCAR2 is also a mediator in this mechanism. The researchers at Augusta University in Georgia who generated these findings have reported that niacin can even spur macrophages, immune cells that often work in concert with microglia, to switch from a proinflammatory form to an anti-inflammatory one. The team is currently carrying out a clinical trial to test niacin treatment on this neurodegenerative disease.
Niacin has not yet been tested in humans in the context of Alzheimer’s disease. Jean Harry, a neurotoxicologist at the National Institute of Environmental Health Sciences in Durham, North Carolina, says that while the formulation of niacin used by Moutinho and colleagues is a drug approved for consumption, “trying to get enough of a substance into the brain parenchyma from some sort of systemic dosing is not always easy, even for things that do get across the blood-brain barrier.” Thus, she adds, when translating this over to humans, researchers will need to think about the possible side effects of dosing at levels where nicotinic acid gets into the brain, and how that could affect peripheral macrophages.
Landreth says that his team has recently submitted a grant proposal to plan a two-year pilot clinical trial that aims to assess whether nicotinic acid supplements would result in changes in biomarkers of Alzheimer’s disease and to “validate that we are getting nicotinic acid into the brain at physiologically relevant levels.” He adds that the side effects currently associated with nicotinic acid treatment, such as skin flushing, are “easily addressable.”
“We’re pretty excited about this,” concludes Landreth.
Niacinamide: niacin’s sister molecule also proposed as treatment for Alzheimer’s
Niacinamide, also known as nicotinamide, is another form of vitamin B. Although the molecular structure of niacin and niacinamide differs, both play an essential role in the biosynthesis of NAD and its reduced form NADH, molecules involved in the synthesis of ATP, which cells use as a ready energy source.
Niacinamide has also been associated with protective effects in the central nervous system, although via different mechanisms than those described for niacin. For instance, in a mouse model of Alzheimer’s, niacinamide treatment reduced neuronal vulnerability to amyloid-β toxicity and improved cognitive performance, mainly by enhancing brain bioenergetics. This form of vitamin B has also been reported to reduce a species of tau protein in a mouse model of Alzheimer’s. The body of research linking niacinamide with beneficial outcomes has motivated a few ongoing clinical trials, mainly in the US.
In an email, Indiana University School of Medicine researcher Miguel Moutinho explains that in the context of Alzheimer’s disease, “in the brain . . . activation of HCAR2 is one of the main mechanisms through which nicotinic acid acts . . . while nicotinamide is probably more associated with production of NAD.”
Clarification (April 12): The text has been updated to reflect David Morgan's role with Biogen.