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      Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals 1 2 3 4 5

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          Abstract

          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.

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          Most cited references24

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          Homocysteine lowering with folic acid and B vitamins in vascular disease.

          In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.). Copyright 2006 Massachusetts Medical Society.
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            Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

            Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Referral population to a hospital clinic between July 1988 and April 1996. Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.
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              Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial.

              Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50-70 years with raised plasma total homocysteine and normal serum vitamin B12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance. Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 mug daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov with trial number NCT00110604. Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0.132, 95% CI 0.032 to 0.233), information processing speed (0.087, 0.016 to 0.158) and sensorimotor speed (0.064, -0.001 to 0.129) were significantly better in the folic acid group than in the placebo group. Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.
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                Author and article information

                Journal
                Am J Clin Nutr
                Am. J. Clin. Nutr
                ajcn
                The American Journal of Clinical Nutrition
                American Society for Nutrition
                0002-9165
                1938-3207
                August 2014
                25 June 2014
                25 June 2014
                : 100
                : 2
                : 657-666
                Affiliations
                [1 ]From the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom (R Clarke, DB, SP, SL, JA, JH, and R Collins); the Department of Human Nutrition, University of Otago, Dunedin, New Zealand (MS); the Section for Pharmacology and Department of Public Health and Primary Care, University of Bergen, Bergen, Norway (SJPME); the Department of Epidemiology, School for Public Health and Primary Care, CAPHRI, Maastricht University Medical Centre, Maastricht, Netherlands (SJPME); the Section of Hematology and Coagulation, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden (CL); the Division of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom (DJS); the School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia (GJH); the Population Health Research Institute and Department of Medicine, McMaster University, Hamilton, Canada (EL); the Department of Neurology, Western University, London, Canada (JDS); Unité de Recherche en Epidémiologie Nutritonnelle (UREN), Sorbonne-Paris-Cité, UMR Inserm U557, France (PG); Inra U1125, Paris, France (PG); Cnam, Paris, France (PG); Université Paris 13, CRNH IdF, Bobigny, France (PG); the Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, Netherlands (LCdG); the Department of Nutrition and Public Health Intervention Research, London School of Hygiene and Tropical Medicine, London, United Kingdom (ADD); and the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA (FG).
                Author notes
                [2]

                Investigators in the B-Vitamin Treatment Trialists’ Collaboration are listed in Appendix A after the References.

                [3]

                R Clarke, DB, and SP contributed equally to this article.

                [4]

                Supported by the British Heart Foundation, the UK Medical Research Council, Cancer Research UK, and the UK Food Standards Agency (N05072) and Department of Health. Sources of funding for the individual trials are described in their separate publications. The Clinical Trial Service Unit and Epidemiological Studies Unit, where the B-Vitamin Treatment Trialists’ Collaboration Secretariat is located, has a policy of not accepting fees, honoraria, or paid consultancies directly or indirectly from industry. It receives funding from the British Heart Foundation, UK Medical Research Council, and Cancer Research UK. This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

                [5 ]Address correspondence to R Clarke, Clinical Trial Service Unit and Epidemiological Studies Unit, Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. E-mail: robert.clarke@ 123456ctsu.ox.ac.uk .
                Article
                076349
                10.3945/ajcn.113.076349
                4095663
                24965307
                13eb31fd-1cf5-428a-8a6b-ae4182f69922

                This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 28 September 2013
                : 8 May 2014
                Page count
                Pages: 10
                Categories
                Nutritional Epidemiology and Public Health

                Nutrition & Dietetics
                Nutrition & Dietetics

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