Vitamin D May Lower the Risk of Dementia
By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationship to this field of study.
You saw the title and probably said to yourself "Really? Another use for the star vitamin, vitamin D?" Indeed; it's true. Branching out from bones, autoimmune diseases, and cancer, the neuroprotective effects of vitamin D are intriguing, and the clinical trials examining associations and causation of vitamin D and dementia are worth our attention. Previous issues of Alternative Medicine Alert (see July 2010, December 2010, and February 2011 issues) have examined the connection between serum 25-hydroxyvitamin D (25(OH)D) or vitamin D supplementation and various medical conditions. Below, however, is a summary of the brain-relevant mechanisms and research, including usable pearls and what future neurological data may help to refine this aspect of the 21st century's favorite micronutrient.
Physiology and Mechanism of Action
There are many proposed connections between serum 25(OH)D, more physiologically active forms of vitamin D, and central nervous system physiology. First of all, and a crucial component of the relevancy of vitamin D's effects on the brain, vitamin D receptors (VDR) are found in neuronal and glial cells crucial for cognition.1 For example, the cerebral cortex and cerebellum have vitamin D receptors and 1-alpha-hydroxylase (an enzyme that acts upon vitamin D), possibly indicating that the brain is able to convert 25(OH)D to more active forms locally.2,3 Interestingly, people with Alzheimer's disease (AD) may have a reduction in the expression of VDR in different layers of the hippocampus,3,4 further evidence of a role for vitamin D in memory.
Animal and basic science research have found that vitamin D may prevent the degeneration of neurons by helping to clear beta-amyloid, assist in detoxification of nerve tissue, maintain calcium homeostasis, and through the expression of neurotrophic factors such as neurotrophin-3 and glial cell line derived neurotrophic factor.1,5,6 More specifically, vitamin D may protect the brain directly by decreasing oxidation and inflammation and improvement in neuron health, and indirectly via decreased peripheral artery disease and cerebrovascular and cardiovascular disease.1,6 Vitamin D also may provide neuroprotection by inhibiting nitric oxide synthase and upregulating enzymes involved in glutathione synthesis.1,6
Clinical Research
Clinical research relevant to vitamin D and dementia falls generally into two main categories. First, there are cross-sectional retrospective studies looking to find an association, and relative risk (RR), between vitamin D intake or serum 25-hydroxyvitamin D (25(OH)D) and either rates of dementia or cognitive impairment. Second, case-control retrospective or prospective studies exist, usually examining cohorts of people ingesting different amounts of vitamin D and connections with rates of dementia. In either case, one challenge in comparing the different trials is the variety of neuropsychiatric tests used to quantify cognition and clinical dementia.
A recent review found only five studies, none of which were longitudinal prospective cohort studies (a higher quality of clinical evidence), that had adequate controls and statistical analyses detailing 25(OH)D connections with cognitive performance.3 Overall, the results were mixed, with some trials finding a connection, and others failing to find any effect of vitamin D levels on cognitive performance. The trials, as mentioned above, used a variety of clinical tests to assess cognition; this could explain the disparity in results. Also, some trials controlled for known dementia confounders, and in others there were different cutoffs for what is considered sufficient or insufficient vitamin D levels. The latter point is relevant mostly because some trials did their regression analyses on groups of people within a certain range of serum 25(OH)D (rather than as a continuous variable), so such thresholds will directly affect how the data are analyzed. The most convincing positive associations seemed to be in studies that tested subjects' global cognitive functioning with composite neuropsychiatric tests, rather than specific aspects of cognition (i.e., executive and learning functions), leaving the researchers unable to definitively say which aspects of brain function could be affected by vitamin D.
As an example of the most simple approach to establishing a vitamin D correlation, researchers did a retrospective chart review of 80 patients from a consultative memory clinic, 40 of whom had documented serum 25(OH)D values.7 There was statistically significant positive correlation between serum 25(OH)D and Mini-Mental Status Examination (MMSE) score (P = 0.006), an interesting result but, of course, one that does not begin to explain mechanism nor comment on any possible causation.
Slightly more involved, one cross-sectional study measured the serum 25(OH)D of 100 patients with Parkinson's disease and compared them to values for 100 matched controls and 100 people with AD.8 Focusing on the AD component of the results, 41% of the AD patients had vitamin D insufficiency (< 30 ng/mL), not significantly different from the controls, but interestingly, significantly higher than the Parkinson's disease patients (55%, P = 0.05). The authors offer several explanations for why Parkinson's disease, but not AD, may have such a high proportion of vitamin D insufficiency, including physiologic differences (particularly high concentrations of VDRs in substantia nigra), and reasons why Parkinson's disease patients may get less sun exposure than AD patients. The small sample size of this trial and weak statistical correlation may be the simple explanation for some of the findings.
Patients enrolled in an AD research center were part of a cross-sectional study.9 Eighty ambulatory people (40 with AD, 40 controls) 60 years or older had MMSE, Short Blessed Test (SBT), Clinical Dementia Rating (CDR), mood disorder assessments, and serum 25(OH)D measurements. Among tertiles of 25(OH)D, vitamin D deficiency was correlated with the presence of mood disorders, and one aspect each of SBT (P = 0.0436-0.002) and CDR (P = 0.033), but not with the MMSE.
Other researchers have taken a different track in trying to find the dementia-vitamin D connection. Three hundred eighteen people (75% women, mean age 73 years) receiving home care services in Boston participated in a cross-sectional study and had neuropsychological testing, blood tests, and brain imaging.6 In this group, 76 people had dementia (from any cause), 44% of the total were vitamin D insufficient (< 20 ng/mL), and 15% were deficient (< 10 ng/mL). Patients with vitamin D insufficiency had more than twice the risk of all-cause dementia (odds ratio [OR] = 2.6; confidence interval [CI] = 1.5-4.7), even after adjusting for confounders. Interestingly, the connection to AD specifically became insignificant (OR = 2.7; CI = 0.99-7.2) when an adjustment was made for all possible confounding variables. Also, white matter volumes (as per MRI), an indicator of vascular pathology, were inversely proportional to serum 25(OH)D, confirming what the authors hypothesize as a vascular connection to how vitamin D protects against dementia.
One research group examined the connection between vitamin D deficiency (serum 25(OH)D < 10 ng/mL) and impaired cognition as quantified by a Pfeiffer Short Portable Mini Mental Questionnaire score < 8 in 752 women at least 75 years old in France.4 Detailed information regarding possible confounding variables was collected and incorporated into the statistical analysis. One hundred twenty-nine women had vitamin D deficiency and they also had lower Pfeiffer scores (P < 0.001), though there did not seem to be a linear relationship between these two variables. Overall, even after adjusting for confounding variables, vitamin D deficiency was associated with almost two times the risk of impaired cognition (OR = 1.99, CI = 1.13-3.52, P = 0.017).
Moving over to Italy, researchers examined a database of 858 adults age 65 or older over a 6-year period, comparing rates of substantial cognitive decline (a 3 point drop in the MMSE) in those people with severely deficient serum 25(OH)D (< 10 ng/mL) to those with sufficient levels (at least 30 ng/mL).5 The RR of cognitive decline for people who were severely vitamin D deficient was 1.6 (CI = 1.19-2.00). This change is interesting as the deficient group started at a statistically significant lower MMSE score than the sufficient group (23.7 vs 26.3, P < 0.001). The researchers adjusted for a variety of confounders, finding that the association remained true. Positive aspects of this study include the use of the MMSE, of which many clinicians are familiar, and the prospective design, allowing the researchers to feel more comfortable saying that the association observed was not due to reverse causation. In the discussion, the researchers hypothesized that their results are consistent with some past research showing more of a detrimental effect of low vitamin D on "executive functions" rather than "...other cognitive domains such as memory..." though they clearly state that more research is needed to clarify this.
Not to ignore the male gender, other researchers measured serum 25(OH)D in 1604 community-dwelling men age 65 and over and quantified cognitive function with two standardized tests (the Modified MMSE and the Trail Making Test Part B), following them prospectively for 4.6 years.10 Statistical analyses were done on serum 25(OH)D quartiles, with the lowest quartile < 20 ng/mL and the highest, or reference, quartile > 29.7 ng/mL. An increased odds of cognitive impairment (as per the Modified MMSE) existed across the quartiles, but the trend was not statistically significant and disappeared completely when adjusting for educational level and race. At the follow-up visit, lower serum 25(OH)D and odds for cognitive decline again displayed a trend that was not statistically significant (P = 0.08 for the trend).
Vitamin D Supplementation and Cognition
The medical literature is minimally useful in helping us answer this question; clearly more prospective clinical trials are necessary. One study gave 50,000 IU of vitamin D2 orally three times weekly for 4 weeks to 63 nursing home residents.11 This dosing repleted their serum 25(OH)D adequately, but after the treatment period there was no improvement in animal fluency, clock drawing, nor neuropsychiatric inventory. It is likely that the small sample size and short study duration are factors that may explain the lack of cognitive improvement in this group. No adverse effects were thought to be due to the vitamin D2; several adverse effects occurred in this study, but they were in the comparison group.
Dosage and Administration
A prior issue of Alternative Medicine Alert (see July 2010 issue) reviewed the current dosing recommendations for specific disease conditions. With respect to dementia, it is difficult to draw conclusions from the cross-sectional retrospective trials. The few prospective trials followed serum 25(OH)D, not supplemental vitamin D.
We have options for achieving improvements in serum 25(OH)D that hopefully will translate into improvements in cognition. As our common sense would dictate, and clinical trials support, prudent exposure to sunlight may help. In fact, one study in hospitalized, elderly women with Alzheimer's disease showed improvements in serum vitamin D levels, and an improvement in bone mineral density, with regular sunlight exposure (3615 minutes yearly).12 Baseline 25(OH)D of 9.6 ng/mL increased to 20.9 ng/mL.
Conclusion
There are convincing mechanistic data for how vitamin D could influence neurologic function and help prevent or treat symptoms of dementia. There are VDR in key places in the brain, and vitamin D serves to protect neurons from oxidative damage (via glutathione), inhibit calcium increases that can be damaging to cells, foster neurotrophic factors, and indirectly assist in brain function through vascular effects. Most of our clinical data is looking at associations between serum 25(OH)D and cognitive function as elucidated through primarily cross-sectional research. The results have been all over the map, sometimes, but not always, showing negative effects on MMSE and other tests with low serum 25(OH)D. In some trials, the odds of all-cause dementia and/or AD is higher with vitamin D deficiency, but this also differs study by study. There is debate about the specific type of cognitive function affected by vitamin D. However, there is general consensus about an increased odds of cognitive impairment with vitamin D deficiency (< 10 ng/mL). Absolutely, it would be helpful to see more prospective trials of vitamin D supplementation on the prevention or treatment of dementia.
Recommendation
There are many reasons to avoid vitamin D deficiency, from adverse effects on bone health, to an increased fall risk, and, now, despite the conflicting research, probable adverse effects on neurons that may be connected with cognitive decline, if not overt dementia. One vitamin D expert publicly vouches for its safety, even in moderately high daily doses.13 If he is right, and there are many others who support the need to supplement beyond the paltry RDA, then one clinical track to take, especially in anyone in an at-risk demographic for dementia, would be to test serum 25(OH)D and treat until the patient is in the vitamin D sufficient range (> 30 ng/mL), well out of the range of the increased odds of cognitive impairment that were seen in some of the studies reviewed in this article. Alternatively, prudent sunlight exposure throughout the year, as demonstrated in one trial, could help people to achieve sufficient serum 25(OH)D levels. This approach seems to be safe and possibly effective at avoiding adverse neuron effects from low vitamin D, as we await more well-designed prospective trials that guide our vitamin D prescribing practices.
References
1. Buell JS, Dawson-Hughes B. Vitamin D and neurocognitive dysfunction: Preventing "D"ecline? Mol Aspects Med 2008;29:415-422.
2. Barnard K, Colón-Emeric C. Extraskeletal effects of vitamin D in older adults: Cardiovascular disease, mortality, mood, and cognition. Am J Geriatr Pharmacother 2010;8:4-33.
3. Annweiler C, et al. Vitamin D and cognitive performance in adults: A systematic review. Eur J Neurol 2009;16:1083-1089.
4. Annweiler C, et al. Association of vitamin D deficiency with cognitive impairment in older women: Cross-sectional study. Neurology 2010;74:27-32.
5. Llewellyn DJ, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170:1135-1141.
6. Buell JS, et al. 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010;74:18-26.
7. Przbelski RJ, Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biphysics 2007;460: 202-205.
8. Evatt ML, et al. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008;65:1348-1352.
9. Wilkins CH, et al. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 2006;14:1032-1040.
10. Slinin Y, et al. 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology 2010;74:33-41.
11. Pryzbelski R, et al. Rapid correction of low vitamin D status in nursing home residents. Osteoporos Int 2008;19:1621-1628.
12. Sato Y, et al. Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in hospitalized, elderly women with Alzheimer's disease: A randomized controlled trial. J Bone Miner Res 2005;20:1327-1333.
13. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
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