Clinical Investigation
A Systematic Review and Meta-Analysis of The Effect of Low Vitamin D on Cognition
Alicia M. Goodwill PhD,
Cassandra Szoeke PhD,
Corresponding Author
Alicia M. Goodwill PhD
Institute for Health and Ageing, Australian Catholic University, Melbourne, Victoria, Australia
Address correspondence to Professor Cassandra Szoeke, Department of Medicine (RMH), Level 4, Centre for Medical Research, Royal Melbourne Hospital, Parkville, Victoria 3050 Australia. E-mail: [email protected]Search for more papers by this authorCassandra Szoeke PhD
Institute for Health and Ageing, Australian Catholic University, Melbourne, Victoria, Australia
Department of Medicine (RMH), University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorAlicia M. Goodwill PhD,
Cassandra Szoeke PhD,
Corresponding Author
Alicia M. Goodwill PhD
Institute for Health and Ageing, Australian Catholic University, Melbourne, Victoria, Australia
Address correspondence to Professor Cassandra Szoeke, Department of Medicine (RMH), Level 4, Centre for Medical Research, Royal Melbourne Hospital, Parkville, Victoria 3050 Australia. E-mail: [email protected]Search for more papers by this authorCassandra Szoeke PhD
Institute for Health and Ageing, Australian Catholic University, Melbourne, Victoria, Australia
Department of Medicine (RMH), University of Melbourne, Parkville, Victoria, Australia
Search for more papers by this authorAbstract
Background/Objective
With an aging population and no cure for dementia on the horizon, risk factor modification prior to disease onset is an urgent health priority. Therefore, this review examined the effect of low vitamin D status or vitamin D supplementation on cognition in midlife and older adults without a diagnosis of dementia.
Design
Systematic review and random effect meta-analysis.
Setting
Observational (cross-sectional and longitudinal cohort) studies comparing low and high vitamin D status and interventions comparing vitamin D supplementation with a control group were included in the review and meta-analysis.
Participants
Studies including adults and older adults without a dementia diagnosis were included.
Measurements
Medline (PubMed), AMED, Psych INFO, and Cochrane Central databases were searched for articles until August 2016. The Newcastle-Ottawa Scale and Physiotherapy Evidence Database assessed methodological quality of all studies.
Results
Twenty-six observational and three intervention studies (n = 19–9,556) were included in the meta-analysis. Low vitamin D was associated with worse cognitive performance (OR = 1.24, CI = 1.14–1.35) and cognitive decline (OR = 1.26, CI = 1.09–1.23); with cross-sectional yielding a stronger effect compared to longitudinal studies. Vitamin D supplementation showed no significant benefit on cognition compared with control (SMD = 0.21, CI = −0.05 to 0.46).
Conclusion
Observational evidence demonstrates low vitamin D is related to poorer cognition; however, interventional studies are yet to show a clear benefit from vitamin D supplementation. From the evidence to date, there is likely a therapeutic age window relevant to the development of disease and therefore vitamin D therapy. Longitudinal lifespan studies are necessary to depict the optimal timing and duration in which repletion of vitamin D may protect against cognitive decline and dementia in aging, to better inform trials and practice towards a successful therapy.
Abstract
See editorial by Cedric Annweiler
Supporting Information
| Filename | Description |
|---|---|
| jgs15012-sup-0001-FigS1.docxWord document, 54.3 KB | Figure S1. Funnel plot of log odds ratios against the studies precision (standard error). Open circles and open diamond represent the observed studies and summary effect respectively. Dark circles and diamond represent the imputed studies and adjusted summary effect respectively. |
| jgs15012-sup-0002-TableS1.docxWord document, 23.1 KB | Table S1. Characteristics of Cross-sectional Studies (Partially Adjusted Models) |
| jgs15012-sup-0003-TableS2.docxWord document, 27.2 KB | Table S2. Characteristics of Cross-sectional Studies (Fully Adjusted Models) |
| jgs15012-sup-0004-TableS3.docxWord document, 25.6 KB | Table S3. Characteristics of Longitudinal Studies (Partially Adjusted Models) |
| jgs15012-sup-0005-TableS4.docxWord document, 27.7 KB | Table S4. Characteristics of Longitudinal Studies (Fully Adjusted Models) |
| jgs15012-sup-0006-TableS5.docxWord document, 13.5 KB | Table S5. Characteristics of Interventional Studies |
| jgs15012-sup-0007-TableS6.docxWord document, 19 KB | Table S6. Modified Newcastle-Ottawa Scale (NOS) for Quality Assessment Of Observational Studies |
| jgs15012-sup-0008-TableS7.docxWord document, 12.8 KB | Table S7. Physiotherapy Evidence Database (PEDro) Rating Scale for Quality Assessment of Interventional Studies |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Calcoen D, Elias L, Yu X. What does it take to produce a breakthrough drug? Nat Rev Drug Discov 2015; 14: 161–162.
- 2Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 2011; 10: 819–828.
- 3Etgen T, Sander D, Bickel H, et al. Vitamin D deficiency, cognitive impairment and dementia: A systematic review and meta-analysis. Dement Geriatr Cogn Disord 2012; 33: 297–305.
- 4Balion C, Griffith LE, Strifler L et al. Vitamin D, cognition, and dementia: A systematic review and meta-analysis. Neurology 2012; 79: 1397–1405.
- 5Lam V, Albrecht MA, Takechi R et al. Serum 25-hydroxyvitamin D is associated with reduced verbal episodic memory in healthy, middle-aged and older adults. Eur J Nutr 2016; 55: 1503–1513.
- 6Navarrete-Reyes AP, García-Muñoz I, García-Lara JMA et al. 25-OH-Vitamin D is not associated with cognitive performance among Mexican community-dwelling older persons. J Frailty Aging 2015; 4: 74–79.
- 7Jorde R, Mathiesen EB, Rogne S et al. Vitamin D and cognitive function: The Tromsø study. J Neurol Sci 2015; 355: 155–161.
- 8Darwish H, Zeinoun P, Ghusn H et al. Serum 25-hydroxyvitamin D predicts cognitive performance in adults. Neuropsychiatr Dis Treat 2015; 11: 2217–2223.
- 9Brouwer-Brolsma EM, Dhonukshe-Rutten RAM, van Wijngaarden JP et al. Cognitive performance: A cross-sectional study on serum vitamin d and its interplay with glucose homeostasis in Dutch older adults. J Am Med Dir Assoc 2015; 16: 621–627.
- 10Ahn J-D, Kang H. Physical fitness and serum vitamin d and cognition in elderly koreans. J Sports Sci Med 2015; 14: 740–746.
- 11Llewellyn DJ, Lang IA, Langa KM et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010; 170: 1135–1141.
- 12Matchar DB, Chei C-L, Yin Z-X et al. Vitamin D levels and the risk of cognitive decline in Chinese elderly people: The Chinese longitudinal healthy longevity survey. J Gerontol A Biol Sci Med Sci 2016; 71: 1363–1368.
- 13Bartali B, Devore E, Grodstein F et al. Plasma vitamin D levels and cognitive function in aging women: The nurses' health study. J Nutr Health Aging 2014; 18: 400–406.
- 14Maddock J, Geoffroy M-C, Power C et al. 25-Hydroxyvitamin D and cognitive performance in mid-life. Br J Nutr 2014; 111: 904–914.
- 15van Schoor NM, Comijs HC, Llewellyn DJ et al. Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. Int Psychogeriatr 2016; 28: 759–768.
- 16Overman MJ, Pendleton N, O'Neill TW et al. Evaluation of cognitive subdomains, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D in the European male ageing study. Eur J Nutr 2016. https://doi.org/10.1007/s00394-016-1247-4
- 17Schneider ALC, Lutsey PL, Alonso A et al. Vitamin D and cognitive function and dementia risk in a biracial cohort: The ARIC brain MRI study. Eur J Neurol 2014; 21: 1211.
- 18Slinin Y, Paudel ML, Taylor BC et al. 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology 2010; 74: 33–41.
- 19Annweiler C, Montero-Odasso M, Llewellyn DJ et al. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis 2013; 37: 147–171.
- 20van der Schaft J, Koek HL, Dijkstra E et al. The association between vitamin D and cognition: A systematic review. Ageing Res Rev 2013; 12: 1013–1023.
- 21Shen L, Ji H-F. Vitamin D deficiency is associated with increased risk of Alzheimer's disease and dementia: Evidence from meta-analysis. Nutr J 2015; 14: 76–76.
- 22Villemagne VL, Burnham S, Bourgeat P et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: A prospective cohort study. Lancet Neurol 2013; 12: 357–367.
- 23Ritchie K, Carriere I, Berr C et al. The clinical picture of Alzheimer's disease in the decade before diagnosis: Clinical and biomarker trajectories. J Clin Psychiatry 2016; 77: e305–e311.
- 24Verhagen AP, de Vet HC, de Bie RA et al. The Delphi list: A criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 1998; 51: 1235–1241.
- 25Borenstein M, Hedges LV, Higgins JPT et al. Introduction to Meta-Analysis. Hoboken, NJ: Wiley, 2011.
- 26Carroll JB. Human Cognitive Abilities: A Survey of Factor-Analytic Studies. Cambridge, New York: Cambridge University Press, 1993.
10.1017/CBO9780511571312 Google Scholar
- 27Kueider AM, Tanaka T, An Y et al. State- and trait-dependent associations of vitamin-D with brain function during aging. Neurobiol Aging 2016; 39: 38–45.
- 28Wilson VK, Houston DK, Kilpatrick L et al. Relationship between 25-hydroxyvitamin D and cognitive function in older adults: The health, aging and body composition study. J Am Geriatr Soc 2014; 62: 636–641.
- 29Assmann KE, Touvier M, Andreeva VA et al. Midlife plasma vitamin D concentrations and performance in different cognitive domains assessed 13 years later. Br J Nutr 2015; 113: 1628–1637.
- 30Dhesi JK, Jackson SH, Bearne LM et al. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing 2004; 33: 589–595.
- 31Przybelski R, Agrawal S, Krueger D et al. Rapid correction of low vitamin D status in nursing home residents. Osteoporos Int 2008; 19: 1621–1628.
- 32Dean AJ, Bellgrove MA, 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.
- 33Slinin Y, Paudel M, Taylor BC et al. Association between serum 25(OH) vitamin D and the risk of cognitive decline in older women. J Gerontol A Biol Sci Med Sci 2012; 67: 1092–1098.
- 34Lašaite L, Gailyte I, Puzinas P et al. Vitamin D deficiency is related to worse emotional state. Cent Eur J Med 2011; 6: 558–566.
- 35Hansen AL, Bakke L, Dahl L et al. Vitamin D and executive function: A preliminary report. Percept Mot Skills 2011; 113: 677–685.
- 36Lee DM, Tajar A, Ulubaev A et al. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry 2009; 80: 722–729.
- 37Pettersen JA. Vitamin D and executive functioning: Are higher levels better? J Clin Exp Neuropsychol 2016; 38: 467–477.
- 38Seamans KM, Hill TR, Scully L et al. Vitamin D status and measures of cognitive function in healthy older European adults. Eur J Clin Nutr 2010; 64: 1172–1178.
- 39Tolppanen A-M, Williams DM, Lawlor DA. The association of serum ionized calcium and vitamin D with adult cognitive performance. Epidemiology 2011; 22: 113–117.
- 40McGrath J, Scragg R, Chant D et al. No association between serum 25-hydroxyvitamin D3 level and performance on psychometric tests in NHANES III. Neuroepidemiology 2007; 29: 49–54.
- 41Karakis I, Pase MP, Beiser A et al. Association of serum vitamin D with the risk of incident dementia and subclinical indices of brain aging: The Framingham heart study. J Alzheimers Dis 2016; 51: 451–461.
- 42Peterson A, Mattek N, Clemons A et al. Serum vitamin D concentrations are associated with falling and cognitive function in older adults. J Nutr Health Aging 2012; 16: 898–901.
- 43Kuźma E, Soni M, Littlejohns TJ et al. Vitamin D and memory decline: Two population-based prospective studies. J Alzheimers Dis 2016; 50: 1099–1108.
- 44Annweiler C, Maby E, Meyerber M et al. Hypovitaminosis D and executive dysfunction in older adults with memory complaint: A memory clinic-based study. Dement Geriatr Cogn Disord 2014; 37: 286–293.
- 45Toffanello ED, Coin A, Perissinotto E et al. Vitamin D deficiency predicts cognitive decline in older men and women: The pro.V.A. study. Neurology 2014; 83: 2292–2298.
- 46Pettersen JA, Fontes S, Duke CL. The effects of Vitamin D insufficiency and seasonal decrease on cognition. Can J Neurol Sci 2014; 41: 459–465.
- 47Buell JS, Scott TM, Dawson-Hughes B et al. Vitamin D is associated with cognitive function in elders receiving home health services. J Gerontol A Biol Sci Med Sci 2009; 64: 888–895.
- 48Wilkins CH, Birge SJ, Sheline YI et al. Vitamin D deficiency is associated with worse cognitive performance and lower bone density in older African Americans. J Natl Med Assoc 2009; 101: 349–354.
- 49Menant JC, Close JCT, Delbaere K et al. Relationships between serum vitamin D levels, neuromuscular and neuropsychological function and falls in older men and women. Osteoporos Int 2012; 23: 981–989.
- 50Brouwer-Brolsma EM, van de Rest O, Tieland M et al. Serum 25-hydroxyvitamin D is associated with cognitive executive function in Dutch prefrail and frail elderly: A cross-sectional study exploring the associations of 25-hydroxyvitamin D with glucose metabolism, cognitive performance and depression. J Am Med Dir Assoc 2013; 14: 852.e859–817.
- 51Brouwer-Brolsma EM, Feskens EJM, Steegenga WT et al. Associations of 25-hydroxyvitamin D with fasting glucose, fasting insulin, dementia and depression in European elderly: The SENECA study. Eur J Nutr 2013; 52: 917–925.
- 52Breitling LP, Perna L, Müller H et al. Vitamin D and cognitive functioning in the elderly population in Germany. Exp Gerontol 2012; 47: 122–127.
- 53Perna L, Mons U, Kliegel M et al. Serum 25-hydroxyvitamin D and cognitive decline: A longitudinal study among non-demented older adults. Dement Geriatr Cogn Disord 2014; 38: 254–263.
- 54Groves NJ, Burne THJ. The impact of vitamin D deficiency on neurogenesis in the adult brain. Neural Regen Res 2017; 12: 393–394.
- 55Grubler MR, Marz W, Pilz S et al. Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence. Rev Endocr Metab Disord 2017; 8: 259–272. https://doi.org/10.1007/s11154-017-9417-0.
- 56Beydoun MA, Ding EL, Beydoun HA et al. 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.
- 57Duque G, El Abdaimi K, Macoritto M et al. Estrogens (E2) regulate expression and response of 1,25-dihydroxyvitamin D3 receptors in bone cells: Changes with aging and hormone deprivation. Biochem Biophys Res Commun 2002; 299: 446–454.
