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Objective: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. Methods: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). Results: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) µmol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. Conclusions: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. Classification of evidence: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.

Background: Many randomized controlled trials (RCTs) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers. The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence. Objective: We systematically reviewed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12 status and estimated dose-response relations with the use of a meta-analysis. Design: This systematic review included all RCTs, prospective cohort studies, nested case-control studies, and cross-sectional studies in healthy adult populations published through January 2010 that supplied or measured dietary vitamin B-12 intake and measured vitamin B-12 status as serum or plasma vitamin B-12, methylmalonic acid (MMA), or holotranscobalamin. We calculated an intake-status regression coefficient (β) for each individual study and calculated the overall pooled β and SE (β) by using random-effects meta-analysis on a double-log scale. Results: The meta-analysis of observational studies showed a weaker slope of dose-response relations than the meta-analysis of RCTs. The pooled dose-response relation of all studies between vitamin B-12 intake and status indicated that a doubling of the vitamin B-12 intake increased vitamin B-12 concentrations by 11% (95% CI: 9.4%, 12.5%). This increase was larger for studies in elderly persons (13%) than in studies in adults (8%). The dose-response relation between vitamin B-12 intake and MMA concentrations indicated a decrease in MMA of 7% (95% CI: -210%, -24%) for every doubling of the vitamin B-12 intake. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to seriously alter these results. Conclusion: The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of populations. © 2013 American Society for Nutrition.

ABackground An elevated homocysteine level has been indicated as a risk factor for cardiovascular disease, cognitive decline, and fractures. Supplementation of vitamin B12 and folic acid in order to normalize homocysteine levels might be of substantial public health importance as this might reduce the risk for several age-related conditions. This thesis focuses on two health outcomes frequently associated with elevated homocysteine levels and low levels of vitamin B12 and folate: osteoporosis and cognitive decline later in life. Methods Findings are presented in the context of a model which links dietary intake to biomarkers of nutritional status and subsequently to health outcomes. Two systematic reviews with meta-analyses investigated the current status of knowledge about the association of vitamin B12 intake and status with cognitive function, and the association of homocysteine, vitamin B12 and folate status with bone health. Baseline data of the B-PROOF study were used to assess 1) the association of vitamin B12 intake with status according to four biomarkers (vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA) and homocysteine), 2) the mutual association among these four vitamin B12 biomarkers and 3) the association between homocysteine, vitamin B12 biomarkers, folate and cognitive function. The effect of 2-year daily vitamin B12 (500 μg) and folic acid (400 μg) supplementation on fracture risk was assessed in the B-PROOF study, a large (N=2919) randomized controlled trial in elderly people (aged ≥65 years) with an elevated homocysteine level (≥12.0 µmol/L). Results The systematic review of the literature showed no or inconsistent associations of vitamin B12 intake with cognitive function. Furthermore, serum vitamin B12 was not associated with risk of dementia, global cognition or memory. Studies on MMA and holoTC reported significant associations with risk of dementia, Alzheimer’s disease and global cognition. A meta-analysis showed that serum/plasma vitamin B12 per 50 pmol/L was borderline significantly associated with a lower fracture risk (RR=0.96, 95% CI = 0.92-1.00) and that homocysteine was significantly associated with a higher fracture risk (RR=1.04, 95% CI = 1.02-1.07). Meta-analyses regarding vitamin B12, folate and homocysteine levels and BMD did not show significant associations. In the B-PROOF study a doubling of vitamin B12 intake was associated with 9% higher levels of vitamin B12, 15% higher holoTC, 9% lower MMA and 2% lower homocysteine, saturation of biomarkers occurs with dietary intakes of >5 μg B12. Levels of MMA and homocysteine were higher when vitamin B12 levels were below 330 pmol/L and when holoTC levels were below 100 pmol/L, with a steep elevation when levels of vitamin B12 and HoloTC were below 220 and 50 pmol/L respectively. At baseline, levels of vitamin B12 and holoTC were not associated with cognitive function in any cognitive domain. Levels of homocysteine (β= -0.009), folate (β= 0.002), MMA (β= -0.163) and the wellness score – a vitamin B12 biomarker combination score - (β= 0.048) were significantly associated with the domain of episodic memory. Additionally, homocysteine (β= -0.015) and the wellness score (β= 0.103) were significantly associated with the domain information processing speed. The B-PROOF intervention did not lower the risk of fracture in the total population (HR=0.84, 95% CI = 0.58-1.22). Per protocol subgroup analysis of elderly aged >80 years, showed a lower risk of fracture in the intervention group (HR=0.28, 95% CI 0.10-0.74). We observed more cancer cases in the intervention group (HR=1.55, 95% CI = 1.04-2.30) compared to the placebo group. We cannot rule out the possibility of accelerated cancer progression as a possible negative side effect. Conclusion Our literature reviews and observational data confirm an association of levels of homocysteine, vitamin B12 and folate with cognitive function and fracture risk in elderly. Supplementation with vitamin B12 and folic acid did not lower the risk of fracture in the total study population. Though positive effects on fracture incidence emerged in elderly aged >80 years, these benefits should be weighed against potential risks.

Dat vitaminen en mineralen een positieve invloed uit kunnen oefenen op specifieke lichaamsprocessen is bekend. Twee promovendi van Wageningen Universiteit richten zich op het mogelijke verband tussen vitamine B12, foliumzuur en vitamine D en verschillende leeftijdgerelateerde aandoeningen. De associatie tussen een verhoogd homocysteïnegehalte en een verhoogd risico op fracturen was aanleiding voor een groot trial onderzoek onder ouderen. Dit B-PROOF onderzoek loopt nog.

Dat vitaminen en mineralen een positieve invloed uit kunnen oefenen op specifieke lichaamsprocessen is bekend. Twee promovendi van Wageningen Universiteit richten zich op het mogelijke verband tussen vitamine B12, foliumzuur en vitamine D en verschillende leeftijdgerelateerde aandoeningen. De associatie tussen een verhoogd homocysteïnegehalte en een verhoogd risico op fracturen was aanleiding voor een groot trial onderzoek onder ouderen. Dit B-PROOF onderzoek loopt nog.