Additional evidence from randomized controlled trials In the WHI trial, a subset of participants completed a cognitive test battery, but results of analyses examining the vitamin D intervention’s effect on cognitive function are not yet available.

Observational studies Numerous observational studies that examined associations between vitamin D, serum 25OHD level, or calcium and cognitive function were identified as potentially relevant to DRI development. The greatest number of studies, however, were cross–sectional. No large prospective cohort studies were identified for review, although two analyses of data from large population-based annual surveys and several small cohort studies were included.

Low serum 25OHD levels have been associated with decreased cognitive function in various population groups. A cross–sectional analysis of 752 women 75 years of age and older in the Epidémiologie de l’Ostéoporose (EPIDOS) study found that participants with vitamin D deficiency (serum 25OHD level < 25 nmol/L) had twice the odds of cognitive impairment as other participants (Annweiler et al., 2010). In a population-based cross–sectional study, Lee et al. (2009) examined associations between serum 25OHD level and cognitive function and mood among adult men in a European population. In a spline regression model, significant associations were found between slower information processing and serum 25OHD levels below 35 nmol/L in men ages 40 years and older. In contrast to these findings, a more recent cross–sectional study found that among 1,604 men up to 65 years of age in the Osteoporotic Fractures in Men (MrOS) Study, there were no associations between serum 25OHD level and cognitive impairment, even after adjusting for age, race/ethnicity, education, and other potential confounders (Slinin et al., 2010). This study also examined vitamin D measures as a predictor of subsequent cognitive decline over a mean of 4.6 years of follow-up and found only a borderline significant trend across the first three quartiles of serum 25OHD levels, (≤ 49.75 nmol/L, 50.0 to < 62.75 nmol/L, and 62.75 to < 74.5 nmol/L, respectively), compared with the fourth quartile (≥ 74.5 nmol/L); serum 25OHD level did not predict decline on a timed test of executive function.

In a cross–sectional study of 318 older individuals (mean age 74 years) receiving home health care services, those who received a neurological exam and cranial magnetic resonance imaging (MRI), a lower serum 25OHD level (< 50 nmol/L) was associated with at least twice the odds for all-cause dementia, Alzheimer’s disease, and stroke, as well as increased white-matter hyperintensity volume and prevalence of large-vessel infarcts (Buell et al., 2010). Among three age groups (adolescent, adult, and elderly) examined from NHANES III, no association was found between high serum 25OHD levels and learning or memory, and only the elderly population group was found to have an inverse association between 25OHD level