Neurology. 2012 (Sep 25); 79 (13): 1397–1405 ~ FULL TEXT
Cynthia Balion, PhD, Lauren E. Griffith, PhD, Lisa Strifler, BSc,
Matthew Henderson, PhD, Christopher Patterson, MD, George Heckman, MD,
David J. Llewellyn, PhD, and Parminder Raina, PhD
Department of Pathology and Molecular Medicine,
OBJECTIVE: To examine the association between cognitive function and dementia with vitamin D concentration in adults.
METHODS: Five databases were searched for English-language studies up to August 2010, and included all study designs with a comparative group. Cognitive function or impairment was defined by tests of global or domain-specific cognitive performance and dementia was diagnosed according to recognized criteria. A vitamin D measurement was required. Two authors independently extracted data and assessed study quality using predefined criteria. The Q statistic and I² methods were used to test for heterogeneity. We conducted meta-analyses using random effects models for the weighted mean difference (WMD) and Hedge's g.
RESULTS: Thirty-seven studies were included; 8 contained data allowing mean Mini-Mental State Examination (MMSE) scores to be compared between participants with vitamin D <50 nmol/L to those with values ≥50 nmol/L. There was significant heterogeneity among the studies that compared the WMD for MMSE but an overall positive effect for the higher vitamin D group (1.2, 95% confidence interval [CI] 0.5 to 1.9; I² = 0.65; p = 0.002). The small positive effect persisted despite several sensitivity analyses. Six studies presented data comparing Alzheimer disease (AD) to controls but 2 utilized a method withdrawn from commercial use. For the remaining 4 studies the AD group had a lower vitamin D concentration compared to the control group (WMD = -6.2 nmol/L, 95% CI -10.6 to -1.8) with no heterogeneity (I² < 0.01; p = 0.53).
CONCLUSIONS: These results suggest that lower vitamin D concentrations are associated with poorer cognitive function and a higher risk of AD. Further studies are required to determine the significance and potential public health benefit of this association.
From the Full-Text Article:
This systematic review summarized studies that contained measurements of 25(OH)D and related these to measures of cognition or dementia. The meta-analyses showed individuals with AD had lower 25(OH)D concentrations compared to those without AD, and MMSE scores were lower in individuals with lower 25(OH)D concentrations. The studies included various populations, study numbers, study designs, cognitive tests, confounders, statistical tests, vitamin D methods, and groupings.
Our results differ from 2 other published systematic reviews of vitamin D and cognitive performance. [10, 11] Barnard and Colon-Emeric  suggested that cognitive function measured by MMSE was not associated with 25(OH)D concentration although their conclusions were based on whether the relationship between vitamin D and cognitive test scores in the original studies was statistically significant. Since statistical significance depends on sample size, solely focusing on this criterion could mask a small consistent effect in underpowered studies. As well, several factors limited the comprehensiveness of the prior reviews. Annweiler et al.  searched Medline, PsychINFO, and the Cochrane Library, including all adults, but restricted studies to those which used regression models to investigate the relationship between vitamin D and cognition. The review by Barnard and Colon-Emeric  was 6 months longer, limited databases to PubMed and Web of Science, and included only adults 65 years of age or older. We were more comprehensive in our search strategy (including 5 databases) and in our inclusion criteria which resulted in a larger number of articles screened (3,229 compared to 99 for Annweiler et al.) and studies included (37 compared to 5 for both Annweiler et al. and Barnard and Colon-Emeric). Including a broader range of studies allowed us to perform meta-analyses to clearly identify research gaps and to explore and empirically test potential sources of heterogeneity.
Our meta-analysis comparing cognition (using MMSE) to 25(OH)D provided suggestive evidence of an association; the nature of the relationship is unclear. Most studies did not perform regression analysis to provide an answer to this question. Of the 5 studies that did use regression models, 3 [28, 57, 62] found the relationship to be linear, but 2 found no relationship. [32, 40] This discrepancy may be a function of the type of cognitive measure assessed. Little is known about the function of vitamin D in relationship to the different cognitive domains. The potential for a nonlinear relationship is also a possibility. The relationship between vitamin D and its effect on parathyroid hormone (PTH) is hyperbolic and data from the European Male Ageing Study  found the relationship between 4 cognition test scores and 25(OH)D to exhibit a threshold at 35 nmol/L.
We also found that the method of 25(OH)D measurement was an important determinant of heterogeneity. The CPBA method explained the heterogeneity in the meta-analysis comparing AD to control groups (figure e-2). This method has since been withdrawn from the market due to accuracy issues. The analytical measurement of 25(OH)D is difficult and both between method discrepancies  and within the same method over time  have been described. Standardization and harmonization of 25(OH)D methods is currently being addressed,  but in the interim, it is important to consider the type of analytical method being used when comparing resultst studies.
In addition to the analytical difficulties, assessment of vitamin D status is also a problem as measured vitamin D reflects exposure which may vary throughout the year. Most vitamin D is obtained endogenously when the skin is exposed to UVB. People living above the latitude of 33 ° north will receive sufficient radiation only between 10 am and 3 pm from April to September.  Exogenous sources of vitamin D come from natural (e.g., salmon, sardines, and tuna) and fortified foods (e.g., milk products) as well as supplements. Other factors affecting vitamin D concentration include higher skin pigmentation, older age, and female gender. Genetic factors are also likely to contribute to the vitamin D status.  There is no time-integrated measure of vitamin D concentration or stable biologic response gauge to more accurately assess how much vitamin D a person is exposed to. Many of the studies in this systematic review did not consider factors which can vary vitamin D status. Furthermore, individuals who have cognitive decline are more likely to have poor nutrition and spend less time outdoors. These limitations contribute to the uncertainty in the primary study results and our meta-analyses. It is therefore impossible to rule out reverse causality as an alternative explanation.
This systematic review provides sufficient evidence to warrant further investigation to determine if a cause and effect relationship exists between vitamin D and cognitive impairment. To date, no treatment study has examined this question where both vitamin D and cognition were measured over a sufficient period in a large at-risk population.