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Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.

Background: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. Objective: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged 70 y with mild vitamin B-12 deficiency. Design: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 µg vitamin B-12, 1000 µg vitamin B-12 + 400 µg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. Results: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. Conclusion: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function

Background: Remethylation of homocysteine to methionine can occur through either the folate-dependent methionine synthase pathway or the betaine-dependent betaine-homocysteine methyltransferase pathway. The relevance of betaine as a determinant of fasting total homocysteine (tHcy) is not known, nor is it known how the 2 remethylation pathways are interrelated. Objective: The objectives of the study were to examine the relation between plasma betaine concentration and fasting plasma tHcy concentrations and to assess the effect of folic acid supplementation on betaine concentrations in healthy subjects. Design: A double-blind randomized trial of 6 incremental daily doses of folic acid (50¿800 µg/d) or placebo was carried out in 308 Dutch men and postmenopausal women (aged 50¿75 y). Fasted blood concentrations of tHcy, betaine, choline, dimethylglycine, and folate were measured at baseline and after 12 wk of vitamin supplementation. Results: Concentrations of tHcy were inversely related to the betaine concentration (r = ¿0.17, P <0.01), and the association was independent of age, sex, and serum concentrations of folate, creatinine, and cobalamin. Folic acid supplementation increased betaine concentration in a dose-dependent manner (P for trend = 0.018); the maximum increase (15%) was obtained at daily doses of 400¿800 µg/d. Conclusions: The plasma betaine concentration is a significant determinant of fasting tHcy concentrations in healthy humans. Folic acid supplementation increases the betaine concentration, which indicates that the 2 remethylation pathways are interrelated

Background: A high plasma total homocysteine (tHcy) concentration is a risk factor for cardiovascular disease. The increase in tHcy induced by methionine, the sole dietary precursor of homocysteine, might be modulated by other amino acids present in dietary proteins. Objectives: Our objectives were to compare the postprandial effect of free and dietary methionine on plasma tHcy concentrations and to investigate whether serine and cystine modify the effect of free methionine on tHcy. Design: We conducted a randomized crossover trial in 24 healthy men. Each subject ingested 4 meals on separate days, which were separated by 1 wk. tHcy concentrations were measured in the fasting state and at 2, 4, 6, 8, 10, and 24 h after meal ingestion. The meals were 1) a low-protein meal fortified with 30 mg methionine/kg body wt (reference, denoted by "Met"), 2) meal I additionally fortified with 60.6 mg serine/kg body wt (MetSer), 3) meal I additionally fortified with 12.3 mg cystine/kg body wt (MetCys), and 4) a protein-rich meal containing 30 mg methionine, 60.6 mg serine, and 12.3 mg cystine per kg body wt (Protein). Results: The mean (SD) fasting tHcy concentration was 9.1 +/- 2.7 mumol/L. Mean peak tHcy concentrations were 17.9 +/- 4.5, 14.3 +/- 3.3, 14.8 +/- 3.9, and 11.2 +/- 3.1 mumol/L after Met, MetSer, MetCys, and Protein, respectively. Compared with the mean 24-h area under the tHcy-by-time curve after Met, the mean curves after MetSer, MetCys, and Protein were 37%, 32%, and 77% smaller, respectively (all P <0.0005). Conclusions: Dietary methionine increases tHcy much less than does free methionine. Serine and cystine attenuate the tHcy-raising effect of free methionine. Thus, dietary proteins with a high content of serine or cystine relative to methionine may lead to lower postprandial tHcy responses.

Background: Before dietary folate is absorbed, polyglutamate folates are deconjugated to monoglutamates by folylpoly-gamma-glutamyl carboxypeptidase in the small intestine. The 1561T allele of the glutamate carboxypeptidase II gene (GCPII), which codes for folylpoly-gamma-glutamyl carboxypeptidase, may impair intestinal absorption of dietary folates. Objective: Our aim was to study the bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid across GCPII 1561 genotypes. Design: In a randomized study, 180 healthy adults aged 50-75 y received 323 nmol monoglutamyl folic acid/d (n = 59), 262 nmol heptaglutamyl folic acid/d (n = 61), or placebo (n = 60) for 12 wk. Genotypes were assessed after the intervention. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was calculated by using the changes in serum folate concentration in the treatment groups, after correction for changes in the placebo group and for the administered dose. Results: No subjects with the TT genotype were encountered. At baseline, serum and erythrocyte folate concentrations were higher (P <0.05) in subjects with the CT genotype [16.3 nmol/L (geometric (x) over bar; 95% CI: 13.7,19.3 nmol/L) and 863 nmol/L (735,1012 nmol/L), respectively; n = 19] than in subjects with the CC genotype [ 13.7 (13.1, 14.3) and 685 (652, 721) nmol/L, respectively; n = 161]. Baseline homocysteine concentrations were not significantly different between genotypes. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was not significantly different between subjects with the CC (64%; 52%, 76%) and CT genotypes (70%; 49%, 91%). Conclusions: The 1561 T allele of the GCPII gene does not impair the bioavailability of polyglutamyl folic acid. However, the allele is associated with higher folate status. This association may be explained by yet unidentified factors controlling the expression of the GCPII gene.