Andrew H Ford, MD, FRANZCP, Associate Professor in the Western Australian Centre for Health and Ageing and the School of Psychiatry and Clinical Neurosciences of the University of Western Australia in Perth, Australia, discusses his paper "Vitamins B12, B6 and folic acid for cognition in older men" that was recently published in the Neurology® journal (2010;75:1540-7). He spoke with José Merino, MD, Science Editor of AAN.com.
AAN.com: What is the evidence to support an association between elevated homocysteine levels and cognitive impairment?
Ford: Observational evidence to support the association between elevated homocysteine and cognitive impairment began to emerge in the early 1990s and this body of literature has grown steadily since this time. To date there are at least 77 cross-sectional studies involving 34,238 participants and 14 prospective studies of 8,564 participants, together with a handful of case-control studies reporting an association between cognitive impairment or dementia and elevated homocysteine.1 Observational studies, however, cannot definitively demonstrate causality, as the findings in these studies are susceptible to the possibility of bias, undiscovered confounding, and reverse causality.
AAN.com: How does the combination of vitamins B12 and B6 and folic acid reduce homocysteine?
Ford: Homocysteine is a sulfur-containing amino acid derived from the metabolism of the essential amino acid methionine. Homocysteine is metabolized in three ways: remethylation to methionine via the 5-methyltetrahydrofolate pathway that requires folic acid or vitamin B12; by acquiring a methyl group from betaine in a reaction that mostly occurs in the liver; and the transsulfuration pathway that requires vitamin B6.
The dose of vitamins (B6, B12, and folic acid) needed to decrease homocysteine is fairly low. Folic acid has the greatest effect on homocysteine levels: a daily dose of 0.8 mg reduces the total plasma homocysteine level by approximately 23 percent.2 Higher doses have a minimal additional benefit, and some studies suggest that 0.4 mg daily may have a positive effect. The plasma homocysteine level can be lowered by an additional 7 percent by taking 0.4 mg of vitamin B12 daily. Vitamin B6 appears to have little impact. The vitamins appear to be more effective in people with elevated plasma homocysteine and those with lower vitamin (B12 and folic acid) concentrations. General-purpose multivitamins generally contain less than 0.1 mg of vitamin B12 and 0.4 mg of folic acid.
AAN.com: Please briefly discuss the methodology and major findings of your study.
Ford: Our study recruited 299 elderly hypertensive men (75 and older) to a two-year randomized controlled trial of homocysteine lowering treatment. The men were supplemented with 0.4 mg vitamin B12, 2 mg of folic acid and 25 mg of vitamin B6 or placebo daily. The primary aim of the trial was to determine if vitamin supplementation would improve cognitive performance at two years and whether it would have an impact on longer-term cognitive performance or the incidence of dementia. The results on both accounts were negative. We found that there was essentially no difference between the groups at two years on both primary and secondary outcome measures and the men taking vitamins performed much the same as the placebo group during a telephone cognitive assessment in 2008. There was no difference in the groups when the men were followed up for a diagnosis of dementia by using the West Australian Data Linkage System.
AAN.com: How do your results compare with those of other clinical trials of interventions aimed at reducing total homocysteine levels?
Ford: A number of randomized controlled trials have studied the impact of B-vitamins on cognition, including 11 other trials that have included homocysteine as an outcome. These trials have returned mostly negative results except for the FACIT trial.3 All these trials have investigated the impact of homocysteine lowering vitamin supplementation on cognitive function but, to my knowledge, no trials have examined the impact of these vitamins on reducing the incidence of dementia. Heterogeneity in study size, duration, and participant selection may be partly responsible. Some of these trials have been as short as four weeks in duration and involved less than 50 participants. It is highly likely that the effect size of an intervention such as this will be small and therefore trials will need relatively large numbers to detect a difference between the groups. Prospective studies have also indicated that prolonged exposure to elevated homocysteine is associated with cognitive impairment and therefore the intervention would need to be maintained for a longer period of time. It is thus interesting to note that only the longest trial to date returned positive (although with modest effect sizes) results.3
AAN.com: How do you explain the discrepancy between the strong association between homocysteine levels and cognitive impairment found in observational studies and the lack of effect of homocysteine lowering therapies?
Ford: There are a number of possible explanations for this. The first would be that the findings of observational research are to be explained by confounding, i.e., unmeasured factors in the study that lead to both the elevated homocysteine level and the cognitive changes. Secondly, the findings may in part be due to reverse causality—cognitive impairment occurs first and elevated homocysteine occurs secondary to this (e.g., changes in diet associated with dementia). The probability of reverse causality is less in prospective studies, but these studies are still susceptible to the possibility of undiscovered confounding factors. As indicated above, the heterogeneity of trials completed to date may explain the negative results. It is of course also possible that elevated homocysteine level is not related to cognitive impairment as a risk factor but is merely an innocent bystander or marker of an underlying process responsible for both the elevated homocysteine and the dementia.
AAN.com: A similar effect was found in relation to the risk of stroke. Can you comment on that?
Ford: It is possible that similar reasons may exist to explain the negative finding in stroke research although a number of large, high quality trials have been published in this area. Results from the VITATOPS trial published recently have essentially replicated findings from earlier studies.4 This trial enrolled 8,164 participants and supplemented 4,089 individuals over a median duration of 3.4 years. There was essentially no difference between the groups in the primary endpoint (composite of stroke, myocardial infarction or vascular death)—risk ratio of 0.91, 95%CI 0.82-1.00. The evidence against homocysteine lowering treatment for secondary prevention in cardiovascular disease is a lot more robust than for dementia prevention. There is still need for trials focusing on a reduction in the incidence of dementia rather than changes in cognitive performance.
AAN.com: You postulate that an elevated plasma homocysteine level is not a risk factor for cognitive impairment but a marker of underlying common processes responsible for dementia and high homocysteine levels. What do you think these processes may be?
Ford: There are a number of causes of hyperhomocysteinemia and some of these are also associated with dementia, e.g., advancing age, smoking, alcohol consumption, physical inactivity, and diabetes mellitus. High homocysteine is also a relatively sensitive marker of underlying B-vitamin deficiencies and one of the hypotheses is that the hyperhomocysteinemia preceding dementia is a marker of functional B12 deficiency due to increased brain oxidative stress that may also increase the risk of dementia.
AAN.com: What should clinicians do when faced with a patient with high homocysteine levels who is at risk for cognitive impairment and stroke?
Ford: Unfortunately, at present, there is no evidence from clinical trials to support the practice of homocysteine lowering vitamin supplementation in these patients. However my clinical experience is that many of my older patients are already taking a number of supplements such as B-vitamins, multivitamins and fish oils when seen in our clinics. B-vitamins are cheap and mostly well-tolerated although reports of an increased risk of adverse cardiovascular events5 and colorectal neoplasia6 are concerning. I find that patients tend to make up their own minds when presented with the evidence with some opting to take a supplement. Of course, advice regarding a healthy diet and lifestyle modification where applicable is always beneficial.
1) Smith AD. The worldwide challenge of the dementias: A role for B vitamins and homocysteine? Food Nutr Bull 2008;29(S2):S143-172.
2) Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82:806–12.
3) Durga J, van Boxtel MPJ, Schouten EG et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised double blind, controlled trial. Lancet 2007;369(9557):208-216.
4) VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 2010;9(9):855-865.
5) Bonaa KH, Njolstad I, Ueland PM et al. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. NEJM 2006;354(15)1578-1588.
6) Cole BF, Baron JA, Sandler RS et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297(21):2351-2359.
Dr. Ford has no disclosures to report.
Dr. Merino performed a one-time consultation with staff from Bell, Falla and Associates He is a member of the Stroke Publishing Technology Committee for the journal Stroke and a member of the editorial board of Stroke from 2008-2010.
Dr. Merino has received research support from the cost reimbursement contract between NIH/NINDS Intramural Program and Suburban Hospital to support the clinical, administrative, and technical activities of the NIH Stroke Program at Suburban Hospital. He is also stroke adjudicator for the Women's Health Initiative at NIH.