Antioxidants and vitamins have shown potential as protectors for the brain in numerous animal experiments and human observational studies, but have frustratingly failed to deliver on that promise in Alzheimer disease clinical trials. Now, two new papers add fuel to the fire. In a paper appearing July 12 in Archives of Internal Medicine, researchers led by David Melzer and David Llewellyn at the University of Exeter, England, report the results of the first longitudinal study to look for an association between serum vitamin D levels and cognitive decline. They found that people with the lowest levels of vitamin D were more likely to experience significant cognitive losses over a six-year period than those with higher levels, an outcome that suggests vitamin D supplements should be evaluated in clinical trials. Meanwhile, in a paper in the July Archives of Neurology, researchers led by Monique Breteler of Erasmus Medical Center in Rotterdam, The Netherlands, add to the confusing body of evidence on vitamin E. They present data from a long-term observational trial that strengthen previous findings that vitamin E may play a role in preventing Alzheimer disease.

The vitamin D results are particularly interesting because most Americans have inadequate levels of vitamin D, and levels have dropped over the last decade, according to data from the Third National Health and Nutrition Examination Survey (NHANES III) (see Ginde et al., 2009). At the same time, the level of vitamin D considered adequate for good health has been rising, with many experts now recommending a minimum bloodstream concentration of 75 nmol/L (see Bischoff-Ferrari et al., 2006 and Vieth et al., 2007). This level is difficult to achieve without supplements. Few foods contain vitamin D, with fish oils or fortified foods being the best dietary source. Most vitamin D is made in the body as a result of exposure to sunlight. Vitamin D levels also drop with age, making the elderly more vulnerable to health problems associated with low levels.

Several previous studies have noted an association between low levels of vitamin D and cognitive performance in normal older adults and in those with mild cognitive impairment (see Przybelski et al., 2007 and Llewellyn et al., 2009). Other studies have found the same association in elderly people with AD (see Wilkins et al., 2006 and Oudshoorn et al., 2008). Intriguingly, researchers at University of California, Los Angeles, found that vitamin D could stimulate the clearance of Aβ by macrophages (see Masoumi et al., 2009), suggesting one possible way the nutrient could help prevent AD. All of these investigations, however, were cross-sectional rather than longitudinal, looking at only a single point in time. Participants might be at different stages of dementia, making it hard to draw any conclusions about cause and effect. Dementia might lead to lower vitamin D levels, for example, by making people less active and keeping them indoors more.

To overcome this limitation, first author Llewellyn analyzed data from the InCHIANTI longitudinal, population-based study in Tuscany, Italy. A total of 858 randomly selected people, 65 years or older, volunteered to give blood samples and undergo cognitive testing and medical examinations over a six-year period. Cognitive function was measured with the Mini-Mental State Examination (MMSE) score, as well as with Trail-Making Tests A and B, which measure attention and executive function, respectively. The researchers assessed vitamin D levels by measuring the concentration of the metabolite 25(OH)D in the blood.

Llewellyn and colleagues found that people with 25(OH)D serum levels below 25 nmol/L, who were rated as severely deficient in vitamin D, were 60 percent more likely to show substantial cognitive decline on the MMSE than people with sufficient 25(OH)D levels, and 31 percent more likely to show substantial decline on the Trail-Making Test B. This association held even when the authors adjusted the data to take into account many possible confounding conditions known to be associated with low vitamin D levels, including dementia, impaired mobility, diabetes, stroke, depression, body mass index, education level, age, sex, and other factors.

“The prospective data give us a much stronger argument that vitamin D levels are potentially contributing toward new cases of dementia,” Llewellyn said. “It’s exciting because it means vitamin D is much more likely to have real therapeutic potential.”

The new data are intriguing, said Marian Evatt of Emory University in Atlanta, Georgia. “What’s nice about this study is they took pains to look at a lot of the potential confounds.” Evatt suggested that the next step might be to conduct pilot studies to look at the effectiveness of vitamin D supplements and to examine the safety of higher doses.

Llewellyn and colleagues are currently developing a protocol for a clinical trial that will examine if vitamin D supplements can prevent cognitive decline and dementia. An initial pilot trial will probably involve around 100 healthy elderly people recruited in England, Llewellyn said. At the same time, they are applying for funding to look at vitamin D levels and cognitive performance in other large-scale, longitudinal studies around the world, to ensure that their initial results were not specific to the Italian population they examined. Data from NHANES III already indicate that the association between low vitamin D levels and higher risk of cognitive decline holds in the U.S. population (see press release from ICAD 2010). They also want to look for neuroimaging abnormalities in people with low vitamin D levels, Llewellyn said, to investigate any physical effects the vitamin might be having on the brain.

A critical question that clinical trials should address, Llewellyn said, is to determine what daily dose of vitamin D is optimal for brain health. For treatment of bone health issues, Evatt said, people need to consume 800-1,000 international units daily to get their blood levels above 75 nmol/L, but no one knows if the same amounts will apply to brain health.

Until more data are available, what’s the best advice for people who want to keep their brains as healthy as possible? “If your vitamin D levels are low, you should think about doing something about it,” Llewellyn recommends, “but definitely in the context of an overall healthy lifestyle, including physical activity and a low-fat diet. Vitamin D is not going to be a magic bullet for dementia.”

The second paper addresses the brain health effects of vitamin E, an antioxidant found in vegetable oils, some nuts, spinach and other greens, and fruits such as blueberries. High levels of vitamin E showed promise for lowering AD risk in the six-year population-based Rotterdam study (see ARF related news story on Engelhart et al., 2002). In a highly publicized clinical trial, however, vitamin E supplements showed no benefit for patients with mild cognitive impairment (see ARF related news story on Petersen et al., 2005).

Now, first author Elizabeth Devore, along with the authors of the original Rotterdam study, have analyzed data from that same population of more than 5,000 participants over a 10-year period and found that, although other associations did not hold up, the association of higher vitamin E levels with better cognitive outcomes remained strong.

What might explain the discrepancies in the vitamin E results? No one knows, but Llewellyn points out that clinical trials are usually relatively short-term, and involve people who already have cognitive impairment or dementia, while longitudinal studies follow people, who did not initially have cognitive problems, over many years, and correlate cognitive outcomes with lifestyle or other factors. This may suggest that the critical period when vitamin supplements make a difference in brain health is earlier in life, before cognitive impairment takes hold, Llewellyn speculated. Determination of the critical period, Llewellyn said, is a key question that new research must address.—Madolyn Bowman Rogers


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News Citations

  1. Epidemiology Strengthens Link of Vitamins E and C to Alzheimer’s
  2. Early Intervention Trial Bears Little Fruit, but Sows Hope

Paper Citations

  1. . Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009 Mar 23;169(6):626-32. PubMed.
  2. . Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006 Jul;84(1):18-28. PubMed.
  3. . The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007 Mar;85(3):649-50. PubMed.
  4. . Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys. 2007 Apr 15;460(2):202-5. PubMed.
  5. . Serum 25-hydroxyvitamin D concentration and cognitive impairment. J Geriatr Psychiatry Neurol. 2009 Sep;22(3):188-95. PubMed.
  6. . Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40. PubMed.
  7. . Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(6):539-43. PubMed.
  8. . 1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer's disease patients. J Alzheimers Dis. 2009;17(3):703-17. PubMed.
  9. . Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002 Jun 26;287(24):3223-9. PubMed.
  10. . Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.

External Citations

  1. ICAD 2010

Further Reading

Primary Papers

  1. . Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010 Jul 12;170(13):1135-41. PubMed.
  2. . Dietary antioxidants and long-term risk of dementia. Arch Neurol. 2010 Jul;67(7):819-25. PubMed.