Vitamin D and brain health: an observational and Mendelian randomization study

Shreeya S. Navale, Anwar Mulugeta, Ang Zhou, David J. Llewellyn, Elina Hyppönen

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BACKGROUND: Higher vitamin D status has been suggested to have beneficial effects on the brain. OBJECTIVES: To investigate the association between 25-hydroxyvitamin D [25(OH)D], neuroimaging features, and the risk of dementia and stroke. METHODS: We used prospective data from the UK Biobank (37-73 y at baseline) to examine the association between 25(OH)D concentrations with neuroimaging outcomes (N = 33,523) and the risk of dementia and stroke (N = 427,690; 3414 and 5339 incident cases, respectively). Observational analyses were adjusted for age, sex, ethnicity, month, center, and socioeconomic, lifestyle, sun behavior, and illness-related factors. Nonlinear Mendelian randomization (MR) analyses were used to test for underlying causality for neuroimaging outcomes (N = 23,901) and dementia and stroke (N = 294,514; 2399 and 3760 cases, respectively). RESULTS: Associations between 25(OH)D and total, gray matter, white matter, and hippocampal volumes were nonlinear, with lower volumes both for low and high concentrations (adjusted P-nonlinear ≤ 0.04). 25(OH)D had an inverse association with white matter hyperintensity volume [per 10 nmol/L 25(OH)D; adjusted β: -6.1; 95% CI: -11.5, -7.0]. Vitamin D deficiency was associated with an increased risk of dementia and stroke, with the strongest associations for those with 25(OH)D <25 nmol/L (compared with 50-75.9 nmol/L; adjusted HR: 1.79; 95% CI: 1.57, 2.04 and HR: 1.40; 95% CI: 1.26, 1.56, respectively). Nonlinear MR analyses confirmed the threshold effect of 25(OH)D on dementia, with the risk predicted to be 54% (95% CI: 1.21, 1.96) higher for participants at 25 nmol/L compared with 50 nmol/L. 25(OH)D was not associated with neuroimaging outcomes or the risk of stroke in MR analyses. Potential impact fraction suggests 17% (95% CI: 7.22, 30.58) of dementia could be prevented by increasing 25(OH)D to 50 nmol/L. CONCLUSIONS: Low vitamin D status was associated with neuroimaging outcomes and the risks of dementia and stroke even after extensive covariate adjustment. MR analyses support a causal effect of vitamin D deficiency on dementia but not on stroke risk.

Original languageEnglish
Pages (from-to)531-540
Number of pages10
JournalThe American journal of clinical nutrition
Issue number2
Publication statusPublished or Issued - 4 Aug 2022


  • 25-hydroxyvitamin D
  • brain volume
  • dementia
  • magnetic resonance imaging
  • Mendelian randomization
  • prospective cohort study
  • stroke
  • UK Biobank
  • vitamin D

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics

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