Vitamin D and Brain Health: Smart Ways to Think about Vitamin D

Vitamin D deficiency is now associated with a number of chronic health conditions, thanks to significant research over the last several years. The heart, bones, brain, and immune system are areas already thought to be influenced in one way or another by vitamin D.

This makes sense, if you think about it. The reason that vitamin D is involved in a broad range of bodily functions is that vitamin D plays a significant role in gene expression-a fact highlighted by the wide distribution of vitamin D receptors in human tissue. Some estimates suggest that vitamin D may directly or indirectly affect the expression of up to 1,250 genes-nearly 5% of the total human genome.¹

One emerging interest area for vitamin D is brain health. It appears that sufficient vitamin D intake may benefit those with cognitive impairments like dementia.

First of all, however, it’s important to remember that, despite its media attention, vitamin D is not a “miracle” vitamin.

Being Realistic about Vitamin D

While there is no doubt that vitamin D performs a critical regulatory function in the human body, recent evidence from clinical trials and meta-analyses of existing studies is mixed.

An editorial by Paul Welsh and Naveed Sattar published on April 1, 2014, in the British Medical Journal (BMJ) criticized the use of widespread vitamin D–deficiency testing and supplementation outside of bone health–related conditions. Welsh and Sattar further advocate that doctors “stick to what is proven, encourage better lifestyles in general, and target established risk factors in people at elevated risk” of chronic conditions.²

While, in the authors’ opinion, the research supporting chronic disease prevention is relatively weak in general, their conclusions are also borne out of concern about the “seemingly endless media reports suggesting vitamin D as a panacea for chronic disease,” they wrote. The fear, they said, is that patients may gain a false sense of security, thinking that vitamin D is, essentially, a magic bullet.

This BMJ editorial was published alongside two additional papers exploring vitamin D. In the first, Evropi Theodoratou and colleagues conducted an umbrella review of previously published meta-analyses and review papers of observational data and randomized clinical trials involving vitamin D supplementation.³ Their conclusion is that there is a lack of highly convincing evidence of a clear benefit  of vitamin D for multiple clinical outcomes-although, they noted, they did find associations with some outcomes.

The second paper, authored by Rajiv Chowdhury and colleagues, assessed the association of vitamin D with mortality from cardiovascular, cancer, and other conditions. Chowdhury and colleagues reviewed data from observational and randomized controlled trials.⁴ They found an inverse association between circulating plasma levels of 25-hydroxyvitamin D (a standard marker of vitamin D concentrations) and the risk of death from cardiovascular disease, cancer, and other causes. They also observed that vitamin D3 supplementation significantly reduced overall mortality among adults; however, studies utilizing vitamin D2 supplements showed a slight increased risk of mortality, which the authors said requires further investigation.

Specifically, in studies of supplementation with vitamin D3, the authors found a significant 11% reduction in all-cause mortality. In their BMJ editorial, Welsh and Sattar state that while the 11% decrease in mortality seems remarkable, the studies that Chowdhury and colleagues used were of lesser quality and included fewer participants than comparable trials of blood pressure and statin drugs.²

While the methodological quality of the studies may not have been as robust as the aforementioned drug meta-analyses, and the number of participants did not reach the level of the pooled trials on the drugs, it is still hard to argue that an 11% reduction in all-cause mortality is not significant; this is, actually, a significant reduction by any measure for a simple intervention like vitamin D3.

Furthermore, as its name suggests, vitamin D is a vitamin, which means it’s essential for the normal functioning of the body. Not getting enough vitamin D through the diet can have negative health outcomes. If media reports sensationalizing the research on vitamin D are irresponsible, so, we might argue, might be Welsh and Sattar’s comments calling vitamin D a panacea for chronic disease prevention. Vitamin D is not a panacea; it is an important nutrient. Any hints to the contrary may lead individuals deficient in vitamin D to stop supplementing with the vitamin, at their own health risk.

Instead, the message should be to advocate for an adequate dietary intake of this nutrient through diet and supplementary measures. Given the widespread, documented nature of vitamin D insufficiency in the population, and given vitamin D’s impact on physiological function, there are, indeed, a great number of individuals who would likely strongly benefit from vitamin D supplementation. According to some estimates, nearly 70% of the population in the United States and 86% of the European population are vitamin D insufficient (defined as 25-hydroxyvitamin D levels less than 30 ng/ml), while up to 15% of the general population is severely deficient (less than 10 ng/ml).⁴

There’s More to the Vitamin D Story

A part of the equation not adequately taken into account when it comes to vitamin D research-and research on numerous other nutrients-is individual nutritional requirements. There are instances in which one size may not fit all, so to speak. It’s well-established that numerous factors, including sun exposure, skin color, health status, body mass, and age, can all impact vitamin D conversion, plasma levels, and individual needs.

A recently published paper by Simon Spedding and colleagues from Australia and New Zealand investigated vitamin D requirements based on health status and disease conditions.⁵ The researchers reviewed published studies to determine minimum effective serum 25-hydroxyvitamin D levels for non-skeletal diseases and found that the prevention of most non-bone-health-related conditions call for higher serum vitamin D levels. These conditions include mortality, depression, diabetes, heart disease, respiratory infections, and cancer. The researchers postulated that, just as vitamin D metabolism is tissue dependent, serum levels that signify vitamin D sufficiency in individuals are disease dependent.

Just how different are individual needs when it comes to vitamin D requirements? The authors found, for instance, that certain conditions required two to four times the serum levels for effectiveness, compared to the lower levels needed for bone-health benefits. The researchers further commented that, for many of the trials studying the use of vitamin D for non-skeletal diseases that show a lack of benefit, these trials may suffer from methodological issues, including inadequate dosing and inclusion of participants who already had adequate vitamin D levels at baseline.

The conclusions put forth by Spedding and colleagues shed light on some broader issues with respect to research on the effects of nutritional compounds. While clinical trials demonstrating efficacy for health conditions are desired and are an important piece of the research puzzle, fitting nutrient research into the standard pharmaceutical research model is likely to only tell part of the story. It is akin to fitting a square peg into a round hole, in that nutritional compounds such as vitamin D have broad and diverse mechanisms of action as compared to drug compounds, which have targeted effects.

The benefits of nutrients are also often co-dependent on having sufficient levels of other nutrients. A deficiency in any one of these co-factors can result in the primary nutrient being “ineffective.” So, while certain nutritional compounds may have drug-like efficacy for treating various health conditions, this co-dependency on other factors may create a fuzzier picture when researchers use vitamin D as a single intervention to prevent and treat disease conditions. These considerations aside, research on vitamin D continues to yield promising results, including in the area of cognitive function and brain health.

Brain Health and Cognition

Mathias Shlögl from the University of Basel in Switzerland and Michael Holick of Boston University Medical Center in Boston, MA, recently conducted a review of the literature concerning vitamin D for cognitive function and brain health.⁶ Vitamin D acts beneficially in a number of ways to support brain health, including neuroprotective, neurotrophic (supporting the growth and survival of neurons), and free radical–scavenging effects, as well as supporting vascular health.

When we think of brain health, we think about seniors. The elderly population is at high risk for vitamin D deficiency because of decreased synthesis through the skin and, in general, a decreased dietary intake of vitamin D. And, yet, this is also the population most at risk for developing cognitive impairment and dementia.

Shlögl and Holick found evidence pointing to a doubled risk of cognitive impairment in individuals who were vitamin D deficient. Estimates suggest that between 10%-20% of those aged 65 or older suffer from mild cognitive impairment; thus, the finding that vitamin D sufficiency is associated with better cognitive function is promising.

A further study highlighted in this review found an inverse relationship between serum vitamin D levels and cognitive impairment in nearly 1800 adults in England aged 65 and older. In fact, those with 25-hydroxyvitamin D levels less than 20 ng/ml were found to have a 230% increased risk of cognitive impairment compared to those with 25-hydroxyvitamin D levels higher than 20 ng/ml. Additional studies point to evidence that Alzheimer’s patients had significantly lower vitamin D levels than those without Alzheimer’s disease. Furthermore, those Alzheimer’s disease patients with the lowest vitamin D levels had consistently lower cognitive function scores as assessed by the Mini-Mental Status Exam (MMSE).⁶

Valerie Wilson and colleagues from Wake Forest University School of Medicine in Winston-Salem, NC, conducted a study on 2,777 well-functioning adults for whom they measured serum vitamin D levels and assessed cognitive function at baseline and at a four-year follow-up visit.⁷ The individuals were included in the Health, Aging, and Body Composition Study and resided in Pittsburgh, PA, or Memphis, TN. Using the MMSE to measure cognitive function, the researchers found that low plasma vitamin D levels were associated with worse global cognitive function. In addition, there was a greater decline in MMSE scores over time in those with low plasma vitamin D levels when assessed at the four-year follow-up visit, indicating the relevance of vitamin D to healthy brain function.

Benadetta Bartali and colleagues from Harvard Medical School in Boston, MA, conducted a prospective study involving 1,185 women between 60- and 70-years-old.⁸ These women were a part of the cognitive function sub-study of the Nurses’ Health Study. The subjects had plasma vitamin D levels measured in 1989 or 1990 and then completed a telephone-based assessment of cognitive status approximately nine years later. Six distinct tests made up the cognitive battery, including a telephonic version of the MMSE testing for immediate and delayed recall, category fluency, and recall of digit span backwards (remembering an increasingly long string of numbers backwards). The women with higher vitamin D plasma levels had better cognitive performance on all tests compared to those with lower levels.

Furthermore, a systematic review of studies conducted by researchers from the Department of Geriatrics at University Medical Center Utrecht in The Netherlands assessed the association between vitamin D levels and cognitive function.⁹ After reviewing 25 cross-sectional studies, the authors found that in 18 studies (72%), lower vitamin D levels were statistically significantly associated with a worse outcome on cognitive-function tests or an increased frequency of dementia.

The researchers also identified six prospective studies that they included in the review. In four of the six studies, participants with lower baseline vitamin D levels were shown to have a higher risk of cognitive decline when assessed over a follow-up period of four to seven years.

A Critical Nutrient

Despite the recent criticism from different corners regarding the benefits of vitamin D for prevention of chronic disease, research continues to validate the function of vitamin D in a broad range of areas. An area that is particularly exciting is investigation of vitamin D’s effects on brain health.

Vitamin D is certainly not a magic bullet; in fact very few, if any, panaceas exist. Health is multifactorial and is achieved through a diet rich in all essential nutrients, healthy lifestyle practices, and genetic fortune. However, vitamin D continues to show immense promise to support health and improve well-being as a single intervention, as well as in combination with other therapies.

The association between increased vitamin D levels and reduced risk of mortality is well-documented. As described earlier, Chowdhury and colleagues found a significant 11% reduction in all-cause mortality associated with vitamin D3 supplementation.⁴ Additionally, a study and meta-analysis of prospective studies conducted by Joseph Tomson and colleagues in the United Kingdom examined the association between plasma vitamin D levels and mortality.¹⁰ The authors found that, compared to individuals in the bottom quartile, those in the top quartile of 25-hydroxyvitamin D concentrations had 21% lower vascular mortality and 28% lower all-cause mortality.

Perhaps just as interesting and significant are studies looking at the association between vitamin D deficiency and healthcare costs in military veterans. In an analysis of 886 veterans, vitamin D deficiency was associated with increased utilization of medical services, including more-frequent clinic and emergency room visits. In the vitamin D–deficient group, overall healthcare costs were 39% higher,¹¹ while in a larger sample of veterans (15,340) across six sites in the Southeastern United States, vitamin D deficiency predicted increased healthcare costs at all sites.¹²

Staggering numbers like these stand on their own as advocates for ensuring optimal vitamin D status in the general population. As research methods continue to improve, and our understanding of what constitutes sufficiency of this vitamin in individuals with varying health status increases, studies are likely to bear out the importance of this essential nutrient. In the meantime, given its relatively high safety profile and cost-effective potential to significantly reduce healthcare costs, why not implement an intervention as simple as supplementation with vitamin D as an addition to healthy diet and lifestyle practices?

References

1. Hossein-nezhad A et al., “Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial,” PloS One,vol. 8, no. 3 (2013): e58725.
2. Welsh P et al., “Vitamin D and chronic disease prevention,” British Medical Journal, vol.  348 (April 1, 2014): g2280.
3. Theodoratou E et al., “Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials,” British Medical Journal, vol. 348 (April 1, 2014): g2035.
4. Chowdhury R et al., “ Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies,” British Medical Journal,vol. 348 (April 1, 2014): g1903.
5. Spedding S et al., “Does vitamin D sufficiency equate to a single serum 25-hydroxyvitamin D level or are different levels required for non-skeletal diseases?” Nutrients, vol. 5, no. 12 (December 16, 2013): 5127–5139.
6. Schlögl M et al., “Vitamin D and neurocognitive function,” Clinical Interventions in Aging,vol. 9 (April 2, 2014): 559–568.
7. Wilson VK et al., “Relationship between 25-hydroxyvitamin D and cognitive function in older adults: the health, aging and body composition study,” Journal of the American Geriatrics Society,vol. 62, no. 4 (April 2014): 636–641.
8. Bartali B et al., “Plasma vitamin D levels and cognitive function in aging women: the nurses’ health study,” Journal of Nutrition, Health, and Aging,vol. 18, no. 4 (April 2014): 400–406.
9. Van der Schaft J et al., “The association between vitamin D and cognition: A systematic review,” Ageing Research Reviews,vol. 12, no. 4 (September 2013): 1013–1023.
10. Tomson J et al., “Vitamin D and risk of death from vascular and non-vascular causes in the Whitehall study and meta-analyses of 12,000 deaths,” European Heart Journal,vol. 34, no. 18 (May 2013): 1365–1374.
11. Peiris AN et al., “The relationship of vitamin D deficiency to health care costs in veterans,” Military Medicine, vol. 173, no. 12 (December 2008): 1214–1218.
12. Bailey BA et al., “Vitamin D testing patterns among six Veterans Medical Centers in the Southeastern United States: links with medical costs,” Military Medicine,vol. 177, no. 1 (January 2012): 70–76.