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Homocysteine, Folate, and Vitamins B₆ and B₁₂ Blood Levels in Relation to Cognitive Performance: The Maine-Syracuse Study

From the Department of Psychology, University of Maine, Orono, Maine (M.F.E., M.A.R., P.K.E., S.L.B.); Statistics and Consulting Unit, Boston Department of Mathematics and Statistics, Boston University, Boston, Massachusetts (M.F.E., P.K.E.); Department of Geriatric Medicine, Australian National University, Canberra, Australia (M.M.B.); Department of Pharmacology, University of Oxford, Oxford, UK (C.J.); Neuroscience Division, Medical School, University of Birmingham, Birmingham, UK (Z.N.); MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK (C.J.B.).

Address correspondence and reprint requests to Professor Merrill F. Elias, Boston University, Department of Mathematics, College of Arts and Sciences, 111 Cummington Street, Boston, MA 02215. E-mail: mfelias{at}aol.com

Objective: Our objective was to examine associations among plasma homocysteine concentrations (tHcy), the tHcy-cofactors (folate, vitamins B₆ and B₁₂), and multiple domains of cognitive performance, with statistical adjustment for possible confounds, including cardiovascular disease risk factors (CVD-RF) and cardiovascular disease (CVD).

Methods: Subjects were 812 participants (58% women) of the Maine-Syracuse study who were free of dementia and stroke. Employing a cross-sectional design and multiple regression analyses, fasting concentrations of tHcy and its vitamin cofactors (folate, B₆, and B₁₂) were related to multiple domains of cognitive performance.

Results: With adjustment for age, education, gender, ethnicity, and the vitamins, tHcy was inversely associated with visual-spatial organization, working memory, scanning-tracking, and abstract reasoning. The same results were found with adjustment for age, education, gender, ethnicity, CVD-RF, and CVD. Vitamin cofactors were positively related to cognitive performance, but with adjustment for CVD-RF and CVD, only vitamin B₆ was related to multiple cognitive domains.

Conclusions: The inverse association of tHcy with multiple domains of cognitive functioning is not necessarily dependent on vitamin levels, vitamin deficiency, prevalent CVD risk factors, and manifest CVD. Serum folate, serum B₁₂, and plasma B₆ vitamin concentrations are positively associated with cognitive performance. Investigation of other possible mechanisms (e.g., tHcy neurotoxicity) mediating tHcy associations with cognitive performance is important, as are clinical trials examining the efficacy of folate, vitamin B₆, and vitamin B₁₂ for maintenance of cognitive functioning.

Key Words: cardiovascular risk factors • cognitive performance • folate • homocysteine • vitamin B₆ • vitamin B₁₂

Abbreviations: CVD-RF = cardiovascular disease risk factor; CVD = cardiovascular disease; tHcy = total plasma homocysteine; MSLS = Maine-Syracuse Longitudinal Study; CES-D = Center for Epidemiological Studies Depression Scale; SST = serum separator tube; hs-CRP = high-sensitivity C-reactive protein; HPLC = high-performance liquid chromatography; PCR = polymerase chain reaction; BP = blood pressure; BMI = body mass index; ApoE = apolipoprotein E; nl-tHcy = natural log total homocysteine; nl-folate = natural log folate; nl-B₆ = natural log vitamin B₆.

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