Vitamin D May Promote Brain Health

Long known for promoting bone health, vitamin D has also been linked to brain health. Our experts assess the evidence and explain how to overcome a deficiency.

Paturel, Amy

April/May 2016

In the popular press, vitamin D is hyped as a panacea for everything from overall health and well-being to protecting the brain from disease. With nearly 3,000 articles in the medical literature, it's also a compelling research topic.

Amid the hype, however, experts such as David S. Knopman, MD, FAAN, a professor of neurology at the Mayo Clinic in Rochester, MN, caution that the rush to embrace vitamin D has outpaced available evidence, especially regarding the vitamin's role in neurologic conditions.

To find the middle ground, we spoke to researchers about what the evidence says about vitamin D and brain health—and how much vitamin D is enough.

VITAMIN D BASICS

By definition, the body cannot manufacture vitamins; they must be ingested. But the body can make vitamin D when sunlight shines on the skin's top layer. Whether it's ingested in food, obtained from the sun, or taken as a supplement, vitamin D must still be processed by the liver and kidneys before it becomes “active,” says Tinatin Chabrashvili, MD, PhD, an associate professor of neurology at Tufts University School of Medicine in Boston.

“The active form of vitamin D is not a pure vitamin. It's a hormone that has the ability to turn genes on and off,” says Dr. Chabrashvili. A variety of tissues, including the heart, brain, and immune cells, have vitamin D receptors. Think of vitamin D receptors as your car's gas tank and the active form of vitamin D as the fuel. When you put active vitamin D—also called 25-hydroxyvitamin D, or 25(OH)D—into the tank (and it binds to those receptors), it regulates the expression of at least 900 genes.

“Vitamin D also may protect the brain through its anti-inflammatory and immune-boosting properties,” says Majid Fotuhi, MD, PhD, a neurologist at Johns Hopkins Medicine in Baltimore. In a 2012 study in the Journal of Immunology, researchers at National Jewish Health incubated human white blood cells with varying levels of vitamin D, then exposed them to a molecule known to trigger inflammation. Cells with adequate levels of the nutrient (30 ng/mL) inhibited inflammation better than cells incubated at 15 ng/mL. At even higher levels (50 ng/mL), vitamin D's inhibitory effects on inflammation were more pronounced.

A DEFICIENCY TREND

The sun has proven to be a powerful source for vitamin D. The body can make 10,000 International Units (IU) of vitamin D in just 15 to 30 minutes of unprotected exposure to sunshine. Today, most people spend their time indoors, slather on sunscreen when they're outside, and wear protective clothing such as broad-brimmed hats to reduce skin cancer risk. Plus, a one-time dose of sunshine disappears within a few weeks and likely isn't replenished during winter months. So, perhaps not surprisingly, researchers have noticed a trend toward vitamin D deficiency in recent decades. In fact, according to a 2008 study in the American Journal of Clinical Nutrition, as many as 1 billion people worldwide have a deficiency—and not just in cloudy, rainy places far from the equator. People in California and Florida, for example, may also be vulnerable.

Most experts agree that the optimal blood level of vitamin D (meaning the amount of active vitamin D circulating in the bloodstream) is between 20 and 40 ng/mL. Yet, according to some estimates, nearly 70 percent of Americans fall short of the 30 ng/mL threshold, and up to 15 percent are severely deficient (less than 10 ng/mL). Those numbers skyrocket among people with brain disorders. An estimated 80 percent of people with multiple sclerosis (MS) and 90 percent of people with dementia have vitamin D levels of less than 20 ng/mL. Researchers suspect people with Parkinson's or Alzheimer's disease and the elderly are similarly deficient.

“Aging reduces skin thickness, which inhibits the body's ability to make vitamin D from sun exposure,” says David Llewellyn, PhD, a senior research fellow in clinical epidemiology at the University of Exeter in the United Kingdom. Coupled with reduced dietary intake of vitamin D and the impaired intestinal absorption that also accompanies aging, deficiency is almost inevitable.

A MULTIPLE SCLEROSIS LINK

Over the past several years, vitamin D deficiency has been associated with an increased risk of such brain-related disorders as Parkinson's disease, dementia, and, most compellingly, MS. In a 2004 analysis of data on more than 187,000 women enrolled in the Nurses' Health Study published in Neurology, a team of Harvard researchers reported that those who ingested more vitamin D from food (approximately 700 IU/day) had a 41 percent lower risk of MS compared to women with lower intakes; those who took vitamin D supplements (400 IU/day or more) had a 33 percent reduced risk of developing the disease compared to those who did not.

In a 2006 study published in the Journal of the American Medical Association, Harvard researchers discovered that people, specifically white people, whose blood levels of vitamin D were above 40 ng/mL had a 62 percent lower risk of developing MS. More recently, researchers have linked higher blood levels of vitamin D with reduced risk of relapse, less active lesions on MRI, and possible neuroprotective effects. Although it's not clear what vitamin D's role is in relation to MS, one hypothesis is that the vitamin has an impact on the immune system and that people with MS may have faulty vitamin D receptors.

PRELIMINARY ASSOCIATION WITH PD

Most evidence on the link between vitamin D and Parkinson's disease (PD) has been from animal studies, but recent human trials have also uncovered a connection. In a July 2010 study published in Archives of Neurology, for example, Finnish researchers suggested that chronically deficient levels of vitamin D may play a role in the development of PD. Based on the Mini-Finland Health Survey, the researchers followed up with 3,173 men and women without PD and found that those with higher blood levels of vitamin D showed a reduced risk of the disease. A 2008 study by Emory University researchers also published in Archives of Neurology found that more people with PD (55 percent) had a vitamin D deficiency than a control group (36 percent). Scientists don't know how or even if vitamin D levels affect Parkinson's risk, but the findings are generating interest in more research.

Low vitamin D concentrations have also been associated with the development of dementia and Alzheimer's disease. In a 2014 Neurology study of more than 1,600 people enrolled in the Cardiovascular Health Study, for example, those who were deficient in vitamin D had double the risk of developing dementia.

“Studies suggest that vitamin D protects against dementia by helping to break down and sweep out Alzheimer's disease-related proteins and by enhancing blood flow to the brain,” says Dr. Llewellyn.

Dr. Llewellyn's own research, published in Neurology in 2014, revealed that compared to people with “optimum” vitamin D levels (above 20 ng/mL), those with the lowest levels (less than 10 ng/mL) not only performed more poorly on a battery of mental tests, they also had more than double the risk of developing Alzheimer's disease and other types of dementia. Even a moderate deficiency (10 to 20 ng/mL) was associated with a 53 percent increased risk of developing dementia and a 69 percent increased risk of developing Alzheimer's disease compared to those who had adequate levels (more than 20 ng/mL).

Still, Dr. Knopman questions the link between vitamin D deficiency and age-related diseases. “Alzheimer's and dementia increase with advancing age and vitamin D deficiency increases with advancing age, so you have to wonder if the relationship is incidental or if there's a causal mechanism at play,” he says. Scientists are trying to tease out the findings.

SUNSHINE AND SUPPLEMENTS

Popping a vitamin D supplement may seem like a quick and easy fix, but it's not clear that supplements make a difference. “Many studies show a strong connection between low levels of vitamin D and neurologic disease, but not many show that if you increase vitamin D levels you reverse those deficits,” says Dr. Fotuhi.

Part of the problem is that countless processes affect vitamin D levels, including sunlight exposure, dietary habits, and functioning vitamin D receptors. “If patients have a problem at the receptor level, giving them more vitamin D isn't going to change their blood level,” says Dr. Chabrashvili. Similarly, the benefits of supplements also depend on having sufficient levels of other nutrients, including calcium, magnesium, and zinc. A deficiency in any one of these can render vitamin D ineffective. In the same way calcium needs vitamin D for absorption, vitamin D needs these nutrients to bind to vitamin D receptors.

Still, experts agree that most Americans would do well to maintain a healthy, balanced diet; get sufficient “safe” sunshine; and recognize that no vitamin or supplement is a magic bullet for a healthy brain.

What's Your Vitamin D Status?

Many Americans aren't getting enough vitamin D. Here's how to make sure you aren't one of them.

Get tested. A simple blood test can measure levels of vitamin D. Based on your results, you and your physician can decide whether you need to take supplements.

Don't shun the sun. 

For most people, sitting in the sun for 15 to 20 minutes without using sunscreen is sufficient to achieve blood levels of vitamin D that hover around 30 ng/mL. (If you stay in the sun longer than 20 minutes, be sure to apply sunscreen.) But several factors determine how much vitamin D your body produces from the sun, including the time of year, the time of day, where you live, and what type of skin you have. According to a study published in The American Journal of Clinical Nutrition in 2004, people with lightly pigmented skin, for example, are approximately five times more efficient than those with darker skin at synthesizing vitamin D from the sun.

Choose vitamin D-rich foods. 

Natural food sources of vitamin D include fatty fish, egg yolks, and certain mushrooms, but you have to eat a lot of them to overcome a deficiency. Coupled with adequate sunshine, fortified foods (including milk, yogurt, cereal, and orange juice) can also help you achieve your daily quota.

Take a supplement. 

Opt for vitamin D3 (cholecalciferol), an active form that's more readily absorbed than its vitamin D2 (ergocalciferol) counterpart. Depending on your level of deficiency, experts recommend taking 600 to 4,000 IU daily for a target range of 30 to 50 ng/mL. “If you're significantly deficient, go to a higher dose, but remember that absorption may be an issue,” says Dr. Chabrashvili. “If I give you more, that doesn't mean you will absorb it. There may also be toxicity concerns.”

Reassess regularly. 

If your initial blood test indicates you have a deficiency, your doctor may want to monitor your blood levels every three to six months until you reach the target zone. Those who test at appropriate levels (usually above 30 ng/mL) may repeat testing every two years. Experts recommend using the same lab every time you get tested.

People absorb vitamin D differently, so taking more isn't always more effective.

As the research rolls in, experts continue to refine their dosage recommendations for vitamin D supplements. In 2010, the nonprofit Institute of Medicine (IOM) doubled the upper tolerable intake for adults from 2,000 to 4,000 IU per day. Research suggests that taking substantially larger doses for a short time or periodically (for example, 50,000 IU/week for 8 weeks) does not cause toxicity. In a 2010 study of 75 patients with multiple sclerosis published in Neurology, for instance, daily doses of 10,000 to 14,000 IU of vitamin D per day did not negatively affect blood calcium levels or produce adverse events.

But while some vitamin D is good, more is not necessarily better. There's limited long-term data on intakes above 2,000 IU daily. Even if 3,000 to 4,000 IU daily hasn't been linked with adverse events, scientists don't know if the benefits outweigh the risks because the research hasn't been done yet. And extremely high doses (over 50,000 IU) can cause nausea, vomiting, weakness, and fatigue. More seriously, according to the IOM, it can also raise blood levels of calcium, causing confusion, kidney problems, and heart rhythm abnormalities.

How the Body Converts Vitamin D

Once vitamin D enters the body, either from the sun, food, or supplements, it is processed by both the liver and the kidneys before it becomes active. The liver converts it into 25-hydroxyvitamin D, or 25(OH)D; the kidneys into 1,25-dihydroxyvitamin D, or 1,25(OH)2D. Since 1,25(OH)2D remains in the body for only 15 hours and levels don't drop until there's a severe deficiency, scientists measure levels of 25(OH)D, which stays in the body for 15 days, to assess vitamin D stores. Nevertheless, it's not clear to what extent, if any, 25(OH)D levels reflect health outcomes. Another caveat: Blood levels of 25(OH)D do not account for the amount of vitamin D stored in body tissues.

Scientists continue to study how the nutrient influences brain function. Here's a sampling of some ongoing clinical trials.

Vitamin D Assessment Study (ViDA): University of Auckland researchers followed 5,000 New Zealanders between the ages 50 and 84 to determine why vitamin D levels are low, how those levels impact their risk of disease, and whether taking supplements offers any protection. Results are expected in 2016. http://bit.ly/ViDA-study

Vitamin D and Omega-3 Trial (VITAL): Researchers from Brigham and Women's Hospital are investigating whether taking daily doses of 2,000 IU of vitamin D or a 1 gram supplement of omega-3 fatty acids can reduce the risk of cancer, heart disease, and stroke among healthy people with no history of these diseases. So far, more than 25,874 people have been enrolled. http://vitalstudy.org

The International Polycap Study-3 (TIPS-3): This five-year study is testing whether a combination pill of a low dose of aspirin and vitamin D helps protect against cardiovascular disease, cancers, and fractures among 5,000 men and women from 10 countries with no known heart disease or prior stroke. The study will be conducted by an international group of scientists and physicians and coordinated by the Population Health Research Institute at Hamilton Health Sciences in Ontario, Canada. http://bit.ly/TIPS-3

Finnish Vitamin D Trial (FIND): Finnish researchers are investigating whether a vitamin D supplement (1,600 IU or 3,200 IU) can be the primary prevention of cancers and cardiovascular disease, including stroke, among 18,000 men and women over age 60 and 65, respectively. Recruitment began in 2012 and is ongoing. http://bit.ly/FIND-trial

Vitamin D3-Omega3-Home Exercise-Healthy Ageing and Longevity Trial (DO-HEALTH): This multicenter international research effort involving more than 2,000 men and women over age 70 spans five countries (Switzerland, France, Germany, Portugal, and Austria) and will follow subjects for a total of three years. The goal is to investigate whether a combination of 2,000 IU per day of vitamin D, omega-3, and physical exercise can prevent disease in five primary endpoints, including cognitive decline. Enrollment has ended and results are expected in 2017. http://bit.ly/DO-HEALTH

D-Health: Funded by a research grant from the National Health and Medical Research Council of Australia, this study of 25,000 Australians between the ages of 60 and 84 looks at whether taking a vitamin D tablet changes the risk of a person being diagnosed with heart disease, stroke, cancer, or infections such as the flu. http://bit.ly/D-Health

© 2016 American Academy of Neurology

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