Three Doses of Vitamin D and Cognitive Outcomes in Older Women: A Double-Blind Randomized Controlled Trial

Abstract

Vitamin D may affect cognitive performance, but previous studies are either short term or observational. We conducted a randomized controlled trial of vitamin D supplementation on domain-specific cognitive measures in postmenopausal women. Overweight/obese women with serum 25-hydroxyvitamin D (25OHD) levels less than 30 ng/mL were recruited. Vitamin D3 supplementation (600, 2,000, or 4,000 IU/d) was randomly assigned in a double-blinded manner for 1 year. Serum 25-hydroxyvitamin D, osteocalcin (total and undercarboxylated), amyloid beta, parathyroid hormone, and estradiol were analyzed before and after supplementation. Cognitive tests were administered after treatment. The women (58 ± 6 years; body mass index, 30.0 ± 3.5 kg/m2) had a baseline serum 25-hydroxyvitamin D level of 22.6 ± 5.8 ng/mL that increased to 30.2 ± 5.6, 36.0 ± 4.9, and 40.8 ± 7.0 ng/mL in the 600, 2,000, and 4,000 IU/d groups, respectively (p < .001). Participants taking 2,000 IU/d compared to other doses performed better in learning and memory tests (p < .05), yet the 4,000 IU/d group had a slower reaction time compared to the 600 IU/d group. Multiple regression indicated that serum undercarboxylated osteocalcin predicted tasks associated with reaction time and executive function, whereas body mass index and parathyroid hormone negatively predicted reaction time and executive function (p ≤ .01). These data suggest that vitamin D has differential effects on domain-specific cognitive measures and that a higher dose may negatively affect reaction time.

25-OH Vitamin D Levels and Cognitive Performance: Longitudinal Assessment in a Healthy Aging Cohort

“…Unfortunately, current published intervention trials addressing vitamin D and cognition have not provided a conclusive answer (Dhesi et al, 2004; Przybelski et al, 2008; Dean et al, 2011; Stein et al, 2011; Rossom et al, 2012; Pettersen, 2017; Rutjes et al, 2018; SanMartin et al, 2018; Castle et al, 2019). A recent small intervention trial showed general cognitive status improvement in 16 mild cognitive impaired patients after 18 months of vitamin D supplementation (but not in healthy controls or those already diagnosed with dementia; SanMartin et al, 2018).…”

“…Improved visual memory was observed in healthy Canadian adults with “insufficient” baseline 25(OH)D levels (below 75 nmol/l) that were supplemented with high doses of vitamin D (4,000 IU per day) for 18 weeks, without replication in other cognitive domains (Pettersen, 2017). More recently, in a randomized controlled trial with 69 overweight/obese postmenopausal women with 25(OH)D levels less than 75 nmol/l and divided in three different intervention doses of vitamin D (600, 2,000 or 4,000 IU per day), only the intermediate group performed better in learning and memory tests after 1 year supplementation (Castle et al, 2019). These results reflect the complexity behind any potential vitamin D effect on cognition and the need for better-designed studies, probably including distinct vitamin D insufficiency status populations, supplement doses, exposures periods, age groups and baseline cognitive performances.…”

Genetic, environmental and biomarker considerations delineating the regulatory effects of vitamin D on central nervous system function

“…Benefits are indicated on global cognitive performance (79) and in specific cognitive domains including visuospatial skills, language, working memory, memory recall, concentration and attention (80) . However, other studies indicate that exaggerated levels of vit-D are also associated with poorer cognitive function (25,(81)(82)(83) . Moreover, adding to the complexity of interpretating vit-D-associated CNS effects is the significant potential confounder of reverse causation and in lack of standardisation and heterogeneity of blood vit-D analytics (82,84) .…”

“…A study by Rossom et al (92) failed to demonstrate positive effects of vit-D supplementation in attenuating cognitive dysfunction, or on lowering the risk of dementia when compared with placebo. Moreover, Castle and colleagues recently reported on the differential dosage effects of vit-D on specific cognitive domains in healthy, post-menopausal women whereby higher doses were found associated with poorer reaction time and measures of learning and memory (83) . Furthermore, a recent literature review by Landel et al (72) determined that there was no solid evidence to suggest that exogenous supplementation of vit-D improves cognition in those who already have sufficient serum levels of vit-D.…”

Association of Dietary Vitamin D Intake, Serum 25(OH)D3, 25(OH)D2 with Cognitive Performance in the Elderly

“…A recent cohort in Boston-area Puerto Ricans showed that the association of serum 25(OH)D concentration with individual cognitive test scores was not statistically significant [ 19 ]. However, another recent study in women suggested that higher 25(OH)D concentrations might have negative cognitive effects [ 20 ]. Additionally, currently, no study investigated the dose–response relationships between them.…”