Food and Behaviour Research

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How a simple vitamin B prescription could help people with Alzheimer's

Peter Garrard, Reader in Neurology at St George's, University of London

FAB RESEARCH COMMENT:

A recent 'meta-analysis' - pooling results from a number of randomised controlled treatment trials - concluded that B vitamin supplementation does not reduce the risk of cognitive decline and dementia.

Extraordinarily, however, this much-quoted meta-analysis does not even include the major clinical trial carried out at Oxford University (the OPTIMA - VITACOG study) - which was specifically designed to invesitgate this question.

That study not only showed significant benefits from B vitamin supplementation for slowing cognitive decline in older adults. It also showed significant reductions in physical brain shrinkage in those supplemented with the vitamins (B6, B12 and folate) versus placebo.

While excluding this absolutely key clinical trial, the recent meta-analysis included other trials not even capable of addressing the actual question of whether B vitamins can help prevent 'cognitive aging' - i.e. age-related cognitive decline and dementia. 

Many included trials involved adults too young to be at any significant risk for cognitive decline or Alzheimer's. Others were focused not on dementia but on other conditions. The inclusion criteria for this review did not even require the presence of mild cognitive impairment.

This academic blog article - by an established expert in the field very familiar with the research - explains how publication of this flawed meta-analysis, and its serious misinterpretation, effectively prevented a consortium of leading UK researchers from obtaining funding for studies to follow up the very promising VITACOG findings.

As he emphasises, this misinterpretation is "harmful for medical research, for the cause of dementia prevention and, most of all, for the thousands of individuals who could have benefited from a safe and simple intervention".

Systematic reviews and meta-analyses are at the top of the 'hierarchy' of so-called 'Evidence-Based Medicine' - because when properly conducted, they can provide an unbiased synthesis of the evidence in a given area. 

Unfortunately, when badly designed, conducted or interpreted, they can instead prevent truly evidence-based research from making progress - which is more than unfortunate in areas as important as this one.

For another example of a seriously flawed and potentially misleading meta-analysis - in this case concerning omega-3 fatty acids for the management of depression and other mood disorders - see the following commentary:
 

For further information about the VITACOG trial, and the OPTIMA project of which it formed a part, see:

The VITACOG trial, a preliminary clinical trial in subjects with high plasma homocysteine levels, showed that the brains of those who received B-vitamins shrank significantly less rapidly than those of the placebo group, particularly in areas that are associated with early pathological changes in Alzheimer's.

Such a striking result seemed to indicate the need for a nationwide trial to test whether the outcome would translate into a clinically important disease-modifying effect on the rate of progression in mild cognitive impairment.

The arguments for conducting the trial were overwhelming and, with the assistance of a national network of experts in dementia and clinical trials, I prepared the scientific and economic case for funding.

Opposition to the idea, however, appeared from an unexpected quarter – a meta-analysis of cognitive outcome data taken from completed trials of B vitamins for stroke and heart attack prevention. Somehow, a statistical miscellany of recycled results was rapidly elevated to a status little short of definitive scientific proof.

Meta-analysis can be a powerful way of drawing robust conclusions from the results of an experiment that has been conducted multiple times on small populations.

In the B vitamin case, the numbers included in the meta-analysis were impressive. Yet numbers mean nothing if the data is neither uniform nor directly relevant to the question.

Closer scrutiny revealed that few of the trials focused on dementia, that the ages of patients who took part were well below those associated with the development of Alzheimer’s disease, and that inclusion did not require the presence of mild cognitive impairment. And astonishingly, the results from the VITACOG trial were not included.

Unsurprisingly, the outcome of the pooled analysis was anodyne: neither the treatment nor the placebo group showed any meaningful change on any measure of cognitive status during follow-up. In other words – to quote one of the members of the original VITACOG study team – the analysis merely demonstrated that: “taking B vitamins won’t prevent cognitive decline in those who overall, do not show cognitive decline anyway.”

Yet the absence of any difference between the two treatment arms has been erroneously, widely, and without qualification interpreted as evidence against the benefits of B vitamins in Alzheimer’s disease.

In recently published letters to the journal, I and many colleagues from around the world have pointed out the flaws in the meta-analysis and its harmful misinterpretation: harmful for medical research, for the cause of dementia prevention and, most of all, for the thousands of individuals who could have benefited from a safe and simple intervention.

We remain convinced that the clinical benefits of B vitamins in groups at high risk of Alzheimer’s disease should be allowed to be rigorously tested, but the damage caused by the public misinterpretation of a null study will take a while to unpick.