Vitamin D and cognitive function: The Tromsø Study


      • Serum levels of vitamin D are associated with cognitive function in older subjects.
      • Polymorphisms in the vitamin D receptor are associated with cognitive function.
      • However, randomized controlled trials are needed to establish causality.


      Background and purpose

      There are indications that vitamin D may be important for more than skeletal health, including cognitive function.


      The study was performed in Tromsø, Northern Norway (The Tromsø Study). In a cross-sectional study serum 25-hydroxyvitamin D (25(OH)D) was measured and cognitive function (word recall, digit–symbol coding, finger tapping, Mini Mental State Examination) tested in 4624 subjects; in a prospective study serum 25(OH)D was measured in samples from 1994 and compared to cognitive function tested in 3436 subjects in 2001 and 2044 subjects in 2007; and in a Mendelian randomization study single nucleotide polymorphisms (SNPs) related to vitamin D were evaluated versus cognitive function in 5980 subjects.


      In the cross-sectional study all tests were positively associated with serum 25(OH)D levels with ~5% better performance in subjects in the highest versus lowest serum 25(OH)D quartile. This relation was only seen in subjects older than 65 years. After full adjustment for season, age, gender, body mass index, blood pressure, physical activity and education, the relation was only significant for finger tapping. In the prospective study, serum 25(OH)D from 1994 similarly predicted cognitive function 7–13 years later. In the Mendelian randomization study, only one SNP in the VDR gene (Apal, rs7975232) was significantly associated with cognition (word recall and digit–symbol coding).


      There is an association between serum 25(OH)D and cognition, but randomized controlled trials are needed to establish causality.


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        • Holick M.F.
        Vitamin D, deficiency.
        N. Engl. J. Med. 2007; 357: 266-281
        • Cantorna M.T.
        Vitamin D, multiple sclerosis and inflammatory bowel disease.
        Arch. Biochem. Biophys. 2012; 523: 103-106
        • Littlejohns T.J.
        • Henley W.E.
        • Lang I.A.
        • et al.
        Vitamin D and the risk of dementia and Alzheimer disease.
        Neurology. 2014; 83: 920-928
        • Eyles D.W.
        • Smith S.
        • Kinobe R.
        • Hewison M.
        • McGrath J.J.
        Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.
        J. Chem. Neuroanat. 2005; 29: 21-30
        • Cui X.
        • Gooch H.
        • Groves N.J.
        • et al.
        Vitamin D and the brain: key questions for future research.
        J. Steroid Biochem. Mol. Biol. 2014; (pii: S0960-0760(14)00259-3 [Epub ahead of print])
        • Perna L.
        • Mons U.
        • Kliegel M.
        • Brenner H.
        Serum 25-hydroxyvitamin D and cognitive decline: a longitudinal study among non-demented older adults.
        Dement. Geriatr. Cogn. Disord. 2014; 38: 254-263
        • Llewellyn D.J.
        • Langa K.M.
        • Lang I.A.
        Serum 25-hydroxyvitamin D concentration and cognitive impairment.
        J. Geriatr. Psychiatry Neurol. 2009; 22: 188-195
        • Graf C.E.
        • Rossi C.
        • Giannelli S.V.
        • et al.
        Vitamin D is not associated with cognitive status in a cohort of very old hospitalized patients.
        J. Alzheimers Dis. 2014; 42: S53-S61
        • Theodoratou E.
        • Tzoulaki I.
        • Zgaga L.
        • Ioannidis J.P.
        Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials.
        BMJ. 2014; 348: g2035
        • Anastasiou C.A.
        • Yannakoulia M.
        • Scarmeas N.
        Vitamin D and cognition: an update of the current evidence.
        J. Alzheimers Dis. 2014; 42: S71-S80
        • Kuningas M.
        • Mooijaart S.P.
        • Jolles J.
        • Slagboom P.E.
        • Westendorp R.G.
        • van Heemst D.
        VDR gene variants associate with cognitive function and depressive symptoms in old age.
        Neurobiol. Aging. 2009; 30: 466-473
        • Gezen-Ak D.
        • Dursun E.
        • Bilgiç B.
        • et al.
        Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.
        Tohoku J. Exp. Med. 2012; 228: 189-196
        • Thanassoulis G.
        • O'Donnell C.J.
        Mendelian randomization: nature's randomized trial in the post-genome era.
        JAMA. 2009; 301: 2386-2388
        • Alfred T.
        • Ben-Shlomo Y.
        • Cooper R.
        • et al.
        HALCyon Study Team. Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.
        J. Nutr. 2013; 143: 606-612
        • Beydoun M.A.
        • Ding E.L.
        • Beydoun H.A.
        • Tanaka T.
        • Ferrucci L.
        • Zonderman A.B.
        Vitamin D receptor and megalin gene polymorphisms and their associations with longitudinal cognitive change in US adults.
        Am. J. Clin. Nutr. 2012; 95: 163-178
        • Jacobsen B.K.
        • Eggen A.E.
        • Mathiesen E.B.
        • Wilsgaard T.
        • Njølstad I.
        Cohort profile: the Tromso Study.
        Int. J. Epidemiol. 2012; 41: 961-967
        • Jorde R.
        • Schirmer H.
        • Wilsgaard T.
        • et al.
        Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study.
        PLoS One. 2012; 7: e37295
        • Arntzen K.A.
        • Schirmer H.
        • Wilsgaard T.
        • Mathiesen E.B.
        Impact of cardiovascular risk factors on cognitive function: the Tromsø Study.
        Eur. J. Neurol. 2011; 18: 737-743
        • Lindekleiv H.
        • Erke M.G.
        • Bertelsen G.
        • et al.
        Cognitive function, drusen, and age-related macular degeneration: a cross-sectional study.
        Eye. 2013; 27: 1281-1287
        • Fontbonne A.
        • Berr C.
        • Ducimetière P.
        • Alpérovitch A.
        Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study.
        Diabetes Care. 2001; 24: 366-370
      1. Wechsler D. Wechsler Adult Intelligence Scale. The Psychological Corporation, New York1955
        • Bäckman L.
        • Forsell Y.
        Episodic memory functioning in a community-based sample of old adults with major depression: utilization of cognitive support.
        J. Abnorm. Psychol. 1994; 103: 361-370
        • Palmer K.
        • Bäckman L.
        • Winblad B.
        • Fratiglioni L.
        Detection of Alzheimer's disease and dementia in the preclinical phase: population based cohort study.
        BMJ. 2003; 326: 245
        • Rogne S.
        • Vangberg T.
        • Eldevik P.
        • Wikran G.
        • Mathiesen E.B.
        • Schirmer H.
        Mild cognitive impairment, risk factors and magnetic resonance volumetry: role of probable Alzheimer's disease in the family.
        Dement. Geriatr. Cogn. Disord. 2013; 36: 87-98
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.
        J. Psychiatr. Res. 1975; 12: 189-198
        • Grimnes G.
        • Almaas B.
        • Eggen A.E.
        • et al.
        Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed.
        Eur. J. Endocrinol. 2010; 163: 339-348
        • Rodriguez S.
        • Gaunt T.R.
        • Day I.N.
        Hardy–Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies.
        Am. J. Epidemiol. 2009; 169: 505-514
        • Lewontin R.C.
        The interaction of selection and linkage. I. General considerations; heterotic models.
        Genetics. 1964; 49: 49-67
        • Gaunt T.R.
        • Rodríguez S.
        • Day I.N.
        Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool ‘CubeX’.
        BMC Bioinforma. 2007; 8: 428
        • Jorde R.
        • Sneve M.
        • Hutchinson M.
        • Emaus N.
        • Figenschau Y.
        • Grimnes G.
        Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study.
        Am. J. Epidemiol. 2010; 171: 903-908
        • Balion C.
        • Griffith L.E.
        • Strifler L.
        • et al.
        Vitamin D, cognition, and dementia: a systematic review and meta-analysis.
        Neurology. 2012; 79: 1397-1405
        • Etgen T.
        • Sander D.
        • Bickel H.
        • Sander K.
        • Förstl H.
        Vitamin D deficiency, cognitive impairment and dementia: a systematic review and meta-analysis.
        Dement. Geriatr. Cogn. Disord. 2012; 33: 297-305
        • Bartali B.
        • Devore E.
        • Grodstein F.
        • Kang J.H.
        Plasma vitamin D levels and cognitive function in aging women: the Nurses' Health Study.
        J. Nutr. Health Aging. 2014; 18: 400-406
        • Toffanello E.D.
        • Coin A.
        • Perissinotto E.
        • et al.
        Vitamin D deficiency predicts cognitive decline in older men and women: The Pro.V.A. Study.
        Neurology. 2014; 24 ( 2292-2298
        • Brouwer-Brolsma E.M.
        • de Groot L.C.
        Vitamin D and cognition in older adults: an update of recent findings.
        Curr. Opin. Clin. Nutr. Metab. Care. 2015; 18: 11-16
        • Dean A.J.
        • Bellgrove M.A.
        • Hall T.
        • et al.
        Effects of vitamin D supplementation on cognitive and emotional functioning in young adults — a randomised controlled trial.
        PLoS One. 2011; 6: e25966
        • Przybelski R.
        • Agrawal S.
        • Krueger D.
        • Engelke J.A.
        • Walbrun F.
        • Binkley N.
        Rapid correction of low vitamin D status in nursing home residents.
        Osteoporos. Int. 2008; 19: 1621-1628
        • Vimaleswaran K.S.
        • Cavadino A.
        • Berry D.J.
        • et al.
        Association of vitamin D status with arterial blood pressure and hypertension risk: a Mendelian randomisation study.
        Lancet Diabetes Endocrinol. 2014; 2: 719-729
        • Wilkins C.H.
        • Sheline Y.I.
        • Roe C.M.
        • Birge S.J.
        • Morris J.C.
        Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults.
        Am. J. Geriatr. Psychiatry. 2006; 14: 1032-1040