McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354, 2764-2772

Departments of Human Nutrition, University of Otago, Dunedin, New Zealand.
New England Journal of Medicine (Impact Factor: 55.87). 07/2006; 354(26):2764-72. DOI: 10.1056/NEJMoa054025
Source: PubMed


The results of observational studies suggest that plasma homocysteine concentrations are inversely related to cognitive function in older people. Our objective was to test the hypothesis that lowering the plasma homocysteine concentration improves cognitive function in healthy older people.
We conducted a two-year, double-blind, placebo-controlled, randomized clinical trial involving 276 healthy participants, 65 years of age or older, with plasma homocysteine concentrations of at least 13 micromol per liter. Homocysteine-lowering treatment was a daily supplement containing folate (1000 microg) and vitamins B12 (500 microg) and B6 (10 mg). Tests of cognition were conducted at baseline and after one and two years of treatment. Treatment effects were adjusted for baseline values, sex, and education.
On average, during the course of the study, the plasma homocysteine concentration was 4.36 micromol per liter (95 percent confidence interval, 3.81 to 4.91 micromol per liter) lower in the vitamin group than in the placebo group (P<0.001). Overall, there were no significant differences between the vitamin and placebo groups in the scores on tests of cognition.
The results of this trial do not support the hypothesis that homocysteine lowering with B vitamins improves cognitive performance. (Australian Clinical Trials registry number, ACTR NO 12605000030673.).

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    • "Results revealed no beneficial effect of treatment. Similar conclusions were made by McMahon et al. [37] who investigated the effects of a 2-year daily treatment regimen (1 mg of B9, 0.5 mg of B12, and 10 mg of B6) on Hcy and verbal and nonverbal cognitive function in participants aged 65 years and older with a baseline Hcy level of at least 13 μmol/L. Results revealed reduction in Hcy following treatment at 6, 12, 18, and 24 months after randomisation; however, there was no effect on cognitive function. "
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    ABSTRACT: A copious amount of scientific scrutiny has been dedicated to documenting typical and atypical human ageing, with a substantial body of work focusing upon the impact of lifestyle choices. One such lifestyle choice is that of diet and, in particular, micronutrient ingestion. Epidemiological studies have reported positive associations between B vitamin status and cognitive function, including negative associations between biological markers (i.e., homocysteine) of dysregulated one-carbon metabolism and cognitive function. This has led to a surge of randomised control trials (RCTs) investigations into B vitamin therapy. However, results have continuingly failed to show beneficial behavioural effects. Despite this, results reliably show treatment-related increases in B vitamin level and decreases in homocysteine level—both of which have been identified as risk factors for atypical ageing. In this paper we argue that it would be premature to conclude that B vitamin therapy has no potential and that more research is needed to systematically investigate the optimal dose, the therapeutic “window,” and individual differences in therapy responders and nonresponders. We start with a brief look at one-carbon metabolism and then consider the evidence from epidemiological studies and RCTs in relation to three specific B vitamins: folic acid (B9), pyridoxine (B6), and cobamides (B12).
    Full-text · Article · Mar 2013
    • "Although there is good evidence that folate and vitamins B 6 and B 12 can reduce the levels of homocysteine the evidence that this benefits memory is limited. Unfortunately, a reduction in homocysteine levels does not necessarily result in improved cognition [37]. An interesting exception is the report that in those over 70 years, with mild cognitive impairment (early signs of memory loss), the rate of brain atrophy as measured using structural MRI scans of the brain, was slowed over a period of 2 years by using B vitamins to decrease the levels of homocysteine [38]. "
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    ABSTRACT: The criteria used to establish dietary reference values are discussed and it is suggested that the too often the "need" they aim to satisfy is at the best vaguely specified. The proposition is considered that if we aim to establish optimal nutrition we will gain from considering psychological in addition to physiological parameters. The brain is by a considerable extent the most complex and metabolically active organ in the body. As such it would be predicted that the first signs of minor subclinical deficiencies will be the disruption of the functioning of the brain. The output of the brain is the product of countless millions of biochemical processes, such that if enzyme activity is only a few percentage points less than maximum, a cumulative influence would result. A series of studies of micronutrient supplementation in well-designed trials were reviewed. In metaanalyses the cognitive functioning of children and the mood and memory of adults has been shown to respond to multivitamin/mineral supplementation. Given the concerns that have been expressed about the negative responses to high levels of micronutrients, the implications are discussed of the finding that psychological functioning may benefits from an intake greater than those currently recommended.
    No preview · Article · Jan 2013 · Molecular Nutrition & Food Research
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    • "Our observations seem to align with the human clinical data. Providing high doses of B-vitamins and folate to patients successfully lowers plasma Hcy, with most studies failing to improve cognitive decline (Lewerin et al. 2005; McMahon et al. 2006; Morris et al. 2006; Luchsinger et al. 2007), but see Aisen et al. (2008) and Durga et al. (2007) as exceptions. Alternatively, future approaches aimed at decreasing flux through the methionine pathway, perhaps by inhibition of methyltransferases or S-adenosylhomocysteine hydrolase (Shea et al. 2004; Tchantchou et al. 2004), may have greater therapeutic potential. "
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    ABSTRACT: J. Neurochem. (2011) 116, 82–92. Elevated plasma homocysteine, a risk factor for Alzheimer’s disease, could result from increased production from methionine or by inefficient clearance by folate- and B-vitamin-dependent pathways. Understanding the relative contributions of these processes to pathogenesis is important for therapeutic strategies designed to lower homocysteine. To assess these alternatives, we elevated plasma homocysteine by feeding mutant amyloid precursor protein (APP)-expressing mice diets with either high methionine (HM) or deficient in B-vitamins and folate (B Def). Mutant APP mice fed HM demonstrated increased brain beta amyloid. Interestingly, this increase was not observed in mutant APP mice fed B Def diet, nor was it observed in C57Bl6 or YAC-APP mice fed HM. Furthermore, HM, but not B Def, produced a prolonged increase in brain homocysteine only in mutant APP mice but not wild-type mice. These changes were time-dependent over 10 weeks. Further, by 10 weeks HM increased brain cholesterol and phosphorylated tau in mutant APP mice. Transcriptional profiling experiments revealed robust differences in RNA expression between C57Bl6 and mutant APP mice. The HM diet in C57Bl6 mice transiently induced a transcriptional profile similar to mutant APP cortex, peaking at 2 weeks, following a time course comparable to brain homocysteine changes. Together, these data suggest a link between APP and methionine metabolism.
    Full-text · Article · Nov 2010 · Journal of Neurochemistry
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