BACKGROUND: Nutrient status of B vitamins, particularly folate and vitamin B-12, may be related to cognitive ageing but epidemiological evidence remains inconclusive. OBJECTIVE: The aim of this study was to estimate the association of serum folate and vitamin B-12 concentrations with cognitive function in middle-aged and older adults from three Central and Eastern European populations. METHODS: Men and women aged 45-69 at baseline participating in the Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study were recruited in Krakow (Poland), Kaunas (Lithuania) and six urban centres in the Czech Republic. Tests of immediate and delayed recall, verbal fluency and letter search were administered at baseline and repeated in 2006-2008. Serum concentrations of biomarkers at baseline were measured in a sub-sample of participants. Associations of vitamin quartiles with baseline (n=4166) and follow-up (n=2739) cognitive domain-specific z-scores were estimated using multiple linear regression. RESULTS: After adjusting for confounders, folate was positively associated with letter search and vitamin B-12 with word recall in cross-sectional analyses. In prospective analyses, participants in the highest quartile of folate had higher verbal fluency (p<0.01) and immediate recall (p<0.05) scores compared to those in the bottom quartile. In addition, participants in the highest quartile of vitamin B-12 had significantly higher verbal fluency scores (β=0.12; 95% CI=0.02, 0.21). CONCLUSIONS: Folate and vitamin B-12 were positively associated with performance in some but not all cognitive domains in older Central and Eastern Europeans. These findings do not lend unequivocal support to potential importance of folate and vitamin B-12 status for cognitive function in older age. Long-term longitudinal studies and randomised trials are required before drawing conclusions on the role of these vitamins in cognitive decline.

Center for Health Protection National Institute for Public Health and the Environment PO Box 1 3720 BA Bilthoven The Netherlands

Department of Education University of Oxford 15 Norham Gardens Oxford OX2 6PY UK

Department of Epidemiology and Population Studies Jagellonian University Collegium Medicum Grzegorzecka 20 31 531 Krakow Poland

Department of Epidemiology and Public Health UCL 1 19 Torrington Place London WC1E 7HB UK

Department of Population Studies Institute of Cardiology Lithuanian University of Health Sciences Kaunas LT 50161 Lithuania

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Im Neuenheimer Feld 581 69120 Heidelberg Germany

National Institute of Public Health Srobarova 48 10042 Prague Czech Republic

See more in PubMed

Beydoun M.A., Beydoun H.A., Gamaldo A.A., Teel A., Zonderman A.B., Wang Y.F. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:33. PubMed PMC

Bobak M., Richards M., Malyutina S., Kubinova R., Peasey A., Pikhart H., Shishkin S., Nikitin Y., Marmot M. Association between year of birth and cognitive functions in Russia and the Czech Republic: cross-sectional results of the HAPIEE study. Neuroepidemiology. 2009;33:231–239. PubMed PMC

Clarke R., Birks J., Nexo E., Ueland P.M., Schneede J., Scott J., Molloy A., Evans J.G. Low vitamin B-12 status and risk of cognitive decline in older adults. Am. J. Clin. Nutr. 2007;86:1384–1391. PubMed

Dangour A.D., Allen E., Clarke R., Elbourne D., Fletcher A.E., Letley L., Richards M., Whyte K., Uauy R., Mills K. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial. 2015. Am. J. Clin. Nutr. PubMed PMC

de Lau L.M.L., Refsum H., Smith A.D., Johnston C., Breteler M.M.B. Plasma folate concentration and cognitive performance: Rotterdam scan study. Am. J. Clin. Nutr. 2007;86:728–734. PubMed

de Lau L.M., Smith A.D., Refsum H., Johnston C., Breteler M.M. Plasma vitamin B12 status and cerebral white-matter lesions. J. Neurol. Neurosurg. Psychiatry. 2009;80:149–157. PubMed

Doets E.L., van Wijngaarden J.P., Szczecinska A., Dullemeijer C., Souverein O.W., Dhonukshe-Rutten R.A.M., Cavelaars A.E.J.M., van ‘t Veer P., Brzozowska A., de Groot L.C.P.G.M. Vitamin B-12 intake and status and cognitive function in elderly people. Epidemiol. Rev. 2013;35:2–21. PubMed

Durga J., van Boxtel M.P.J., Schouten E.G., Kok F.J., Jolles J., Katan M.B., Verhoef P. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208–216. PubMed

Duthie S.J., Whalley L.J., Collins A.R., Leaper S., Berger K., Deary I.J. Homocysteine, B vitamin status, and cognitive function in the elderly. Am. J. Clin. Nutr. 2002;75:908–913. PubMed

Elias M.F., Robbins M.A., Budge M.M., Elias P.K., Brennan S.L., Johnston C., Nagy Z., Bates C.J. Homocysteine, folate, and vitamins B-6 and B-12 blood levels in relation to cognitive performance: the Maine-Syracuse study. Psychosom. Med. 2006;68:547–554. PubMed

Feng L., Ng T.P., Chuah L., Niti M., Kua E.H. Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal ageing Study. Am. J. Clin. Nutr. 2006;84:1506–1512. PubMed

Galea S., Tracy M. Participation rates in epidemiologic studies. Ann. Epidemiol. 2007;17:643–653. PubMed

Groves R.M. Nonresponse rates and nonresponse bias in household surveys. Public Opin. Quart. 2006;70:646–675.

Hooshmand B., Solomon A., Kareholt I., Rusanen M., Hanninen T., Leiviska J., Winblad B., Laatikainen T., Soininen H., Kivipelto M. Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J. Intern. Med. 2012;271:204–212. PubMed

Horvat P., Richards M., Kubinova R., Pajak A., Malyutina S., Shishkin S., Pikhart H., Peasey A., Marmot M.G., Singh-Manoux A., Bobak M. Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults. Neurology. 2015;84:287–295. PubMed PMC

Kado D.M., Karlamangla A.S., Huang M.H., Troen A., Rowe J.W., Selhub J., Seeman T.E. Homocysteine versus the vitamins folate, B-6, and B-12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur studies of successful aging. Am. J. Med. 2005;118:161–167. PubMed

Kang J.H., Irizarry M.C., Grodstein F. Prospective study of plasma folate, vitamin B-12, and cognitive function and decline. Epidemiology. 2006;17:650–657. PubMed

Langa K.M., Larson E.B., Karlawish J.H., Cutler D.M., Kabeto M.U., Kim S.Y., Rosen A.B. Trends in the prevalence and mortality of cognitive impairment in the United States: is there evidence of a compression of cognitive morbidity? Alzheimers Dement. 2008;4:134–144. PubMed PMC

McMahon J.A., Green T.J., Skeaff C.M., Knight R.G., Mann J.I., Williams S.M. A controlled trial of homocysteine lowering and cognitive performance. New Engl. J. Med. 2006;354:2764–2772. PubMed

Mooijaart S.P., Gussekloo J., Frolich M., Jolles J., Stott D.J., Westendorp R.G.J., de Craen A.J.M. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-plus study. Am. J. Clin. Nutr. 2005;82:866–871. PubMed

Morris M.S. The role of B vitamins in preventing and treating cognitive impairment and decline. Adv. Nutr. 2012;3:801–812. PubMed PMC

Morris M.S., Selhub J., Jacques P.F. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham heart study. J. Am. Geriatr. Soc. 2012;60:1457–1464. PubMed PMC

O'Leary F., Allman-Farinelli M., Samman S. Vitamin B-12 status, cognitive decline and dementia: a systematic review of prospective cohort studies. Brit. J. Nutr. 2012;108:1948–1961. PubMed

Peasey A., Bobak M., Kubinova R., Malyutina S., Pajak A., Tamosiunas A., Pikhart H., Nicholson A., Marmot M. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006;6:255. PubMed PMC

Plassman B.L., Williams J.W., Burke J.R., Holsinger T., Benjamin S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann. Intern. Med. 2010;153:182–U188. PubMed

Rafnsson S.B. Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies. European journal of nutrition. 2011;50.2:97–106. PubMed

Ramos M.I., Allen L.H., Mungas D.M., Jagust W.J., Haan M.N., Green R., Miller J.W. Low folate status is associated with impaired cognitive function and dementia in the Sacramento area Latino study on aging. Am. J. Clin. Nutr. 2005;82:1346–1352. PubMed

Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5:949–960. PubMed

StataCorp . College Station. StataCorp LP; TX: 2011. Stata Statistical Software.

Stepaniak U., Micek A., Grosso G., Stefler D., Topor-Madry R., Kubinova R., Malyutina S., Peasey A., Pikhart H., Nikitin Y., Bobak M., Pająk A. Antioxidant vitamin intake and mortality in three Central and Eastern European urban populations: the HAPIEE study. Eur J Nutr. 2015:1–14. PubMed PMC

Tangney C.C., Tang Y.X., Evans D.A., Morris M.C. Biochemical indicators of vitamin B-12 and folate insufficiency and cognitive decline. Neurology. 2009;72:361–367. PubMed PMC

Tucker K.L., Qiao N., Scott T., Rosenberg I., Spiro A. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am. J. Clin. Nutr. 2005;82:627–635. PubMed

Wald D.S., Law M., Morris J.K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Brit. Med. J. 2002;325:1202–1206 k. PubMed PMC

Walker J.G., Batterham P.J., Mackinnon A.J., Jorm A.F., Hickie I., Fenech M., Kljakovic M., Crisp D., Christensen H. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms—the Beyond Ageing Project: a randomized controlled trial. Am. J. Clin. Nutr. 2012;95:194–203. PubMed

Risk and protective factors of neurocognitive disorders in older adults in Central and Eastern Europe: A systematic review of population-based studies

Congruent relations between perceived neighbourhood social cohesion and depressive symptoms among older European adults: An East-West analysis