B vitamins: in depth

A study published in the journal PLoS One has found that taking daily high-dose tablets of certain B vitamins reduced the rate of brain shrinkage in people aged over 70 with mild memory problems.

All our brains shrink, especially with age. But the rate of shrinkage is seen to increase in those with mild cognitive impairment, and shrink faster again in Alzheimer’s, suggesting this is part of the disease process. So the observation that brain shrinkage rate can be reduced could be significant, but more work needs to be done to show that.

This finding is of interest because mild cognitive impairment is common – an estimated 1 in 6 people over the age of 70 have MCI – and it’s thought that up to half (so not everyone) go on to develop dementia within 5 years.

The result has been a large amount of media coverage, for example on BBC Online, The Times (subscription required), Daily Mail, and Daily Telegraph.

Despite some subeditors struggling to resist headlines suggesting beating Alzheimer’s or fighting dementia, some points should be stressed (which are actually being widely reported):

1)  It’s one reasonably small trial, although it does show a clear and very interesting difference in the rate of brain shrinkage over a two year period in those who took daily tablets of the combination of three B vitamins.

2)  A larger clinical trial, or certainly longer follow up of these people, is needed to see whether these particular B vitamins actually go on to slow any decline in cognitive ability and progression to dementia and Alzheimer’s before anyone can be confident they will have an effect.

3)  This was a study in people with mild memory problems who are not ill and are able to carry on their normal daily lives, not Alzheimer’s itself.

4)  The tablets included certain B vitamins – B6, B12 and folate – at a high dose; many times what you get in a well balanced diet. At these doses, they must be treated as drugs not just any dietary supplement, and should not be taken without medical advice as there could be side effects. Folate, or folic acid, at high doses and over long periods in some studies has been linked with cancer, for example, though the risk is low and shouldn’t worry anyone being advised to take it, such as pregnant women.

5)The researchers do not suggest people rush out and buy these B vitamins over the counter immediately on the basis of this one study, but call for that larger trial to be done.

The researchers held a press briefing in London communicating their excitement at these results but stressing all these points. Oxford University's David Smith, who led the study, talked about ‘a glimmer of hope’ with these ‘immensely promising results’ after recent failures of high-profile trials of Alzheimer’s drugs, and Helga Refsum said: ‘As a scientist, I would never be happy with the results of just one trial’.

And again, as David Smith says in our news story: ‘These are immensely promising results but we do need to do more trials to conclude whether these particular B vitamins can slow or prevent development of Alzheimer’s.'

Here’s what some other researchers elsewhere have said about the study that echo the interest in the work but offer some appropriate caution about how much we can take from this trial.

Paul Matthews, Professor of Clinical Neurology, Imperial College, London said: ‘This well-conducted study adds substantial new data to previous information suggesting that dietary B vitamins could have beneficial effects on neurodegeneration with aging.

‘Smith and his colleagues studied a mixed group of patients with mild cognitive impairment (MCI) and showed that 2 years of treatment with folic acid and vitamins B12 and B6 slowed rates of brain atrophy. Trends identified in their report suggest that the treatment could slow deterioration of cognition, but this was not demonstrated directly in this small study

‘It is important to appreciate that only some of the patients studied would be expected to develop Alzheimer’s disease; the results therefore should not be interpreted as providing evidence for a new treatment for this most common form of late life dementia.

‘The association between better treatment effects and blood levels of homocysteine - which can be elevated with a deficiency of B vitamins and an increased risk of stroke - raises the question of whether any benefits are related to effects on blood vessels supplying the brain.

‘Although the vitamins used are generally safe and inexpensive, the study should not drive an immediate change in clinical practice. Instead, it sets out important questions for further study and gives new confidence that effective treatments modifying the course of some dementias may be in sight.’ 

Dr Nicholas Timpson, MRC CAiTE Centre (Centre for Causal Analyses in Translational Epidemiology), University of Bristol said: ‘The trial based investigation of a series of homocysteine-lowering B vitamins (including folate and B12) and brain atrophy is of great interest.

'Authors note a reduction in the rate of atrophy in participants randomly allocated to treatment which is itself of great interest, however there are aspects of the work which need to be approached cautiously. These include comparison of observed effects to natural atrophy by age and the actual relationship between cognitive ability and the use of B vitamins. As to the latter of these, there is no direct analysis of cognition and whilst it is alluded to, the lack of this is a clear limitation.

'This work is good evidence of a causal relationship, but the reporting of mean effects in a study such as this does not guarantee impact at the level of the individual given adherence to the same vitamin regime.’ [David Smith points out to me that the study didn’t just report mean effects, but also divided out the results by baseline homocysteine level for example.] 

John Hardy, Professor of Neuroscience, UCL said: ‘The data is very interesting and I have seen it presented. Homocysteine is known to be involved in stroke-related diseases and so involvement in Alzheimer’s disease is plausible. But it is important to note that the study is rather small and needs replicating in a larger study.’ 

Chris Kennard, chair of the Medical Research Council’s Neurosciences and Mental Health Board said: ‘We welcome the findings of this MRC-funded study which bring us a step closer to unravelling the complex neurobiology of ageing and cognitive decline and holds the key to the development of future treatments for conditions like Alzheimer’s disease. However, we must be cautious when recommending supplements like vitamin B as there are separate health risks if taken in too high doses. Further research is required before we can recommend the supplement as a treatment for neurodegenerative diseases, such as Alzheimer’s.’

Figure 1 in the paper outlines the flow of participants through the two-year study. Drop out numbers at each stage are given with some of the reasons. There are some who drop out before the trial, some during, some were excluded, some were diagnosed with cancer, and two died. Of the initial 271 participants, 223 completed the two-year trial and cognitive tests.

But it does appear that there may be a high number of people in the two trial arms (vitamin tablets and placebo) not volunteering for MRIs. Only 168 people had the two MRI scans included in the study and which gave the paper’s main results. While the paper doesn’t describe the reasons for each case (I’m not sure how many papers do), there could be a number of reasons for this in what is an elderly group. It is after all a voluntary scan and some people may not, in the end, like the idea.

On asking David Smith, he adds further: ‘The important point is that in the trial we allowed for the fact that some subjects did not choose an MRI scan by including this in the initial minimization procedure. In other words, no bias was introduced.’

In the end, although these certainly appear promising results, we come full circle to where I started. So I’ll finish with Carl Heneghan’s last line in his blog at the Centre for Evidence-Based Medicine at the University of Oxford:

‘I'd call this an interesting result. But what is needed is a much larger trial, with a well defined clinically significant outcome. Ideally this would be progression to Alzheimer’s disease.’

Update 10 Sep: The Behind the Headlines section of the NHS Choices website has an analysis of the study here.