A new study in PLOS One looks at the effects of taking three B vitamins (folate, B12, and B6) on mild cognitive impairment (MCI). They found that taking these B vitamins over a two year period was associated with a decreased rate of brain atrophy as determined by MRI scanning. Although this is a small study, this is an interesting result that certainly requires further study.

For background, MCI is a common syndrome – affecting 14-18% of those over 70. It is marked by poor memory, concentration, and ability to learn new information, although not severe enough to qualify for a diagnosis of dementia or Alzheimer’s disease (AD). However, 50% of those with MCI do go on to develop Alzheimer’s type dementia. It should be noted that MCI is a clinical syndrome, defined only by symptoms not by underlying cause. Alzheimer’s type dementia is also a clinical syndrome, essentially the presence of dementia without a reversible cause. Alzheimer’s disease is a pathological entity, and requires brain biopsy or autopsy to diagnosis – you need to look at brain under a microscope.

This is a study of MCI, not Alzheimer’s disease. But not surprisingly the popular press is reporting this as a potential treatment for Alzheimer’s disease – that is simply incorrect. This may have implications for AD, but that was not studied.

This study looks at homocysteine – a chemical that increases in the blood if certain B vitamins, mainly folate and B12, are low. High homocysteine levels have been associated with increased risk of stroke, and increased risk of dementia. It has long been known that low B12 levels can cause dementia as well as other neurological damage. The exact role of homocysteine is not clear, however. It also needs to be considered that some MCI and dementia is cause by vascular disease and stroke, and so any correlation between homocysteine and dementia may be through that mechanism.

The authors hypothesized that perhaps reducing homocysteine levels would reduce brain atrophy associated with MCI in the elderly. They studied 85 patients on vitamins B6, B12, and folate compared to 83 patients on placebo. They found overall a 30% decrease in the rate of brain atrophy in the treatment group. Further, in those patients with the highest baseline levels of homocysteine there was a 53% decrease in the rate of brain atrophy. Although this is a small preliminary study, those are fairly dramatic results.

The study did not look at actual cognitive symptoms, just brain atrophy. It also did not look at the rate of progression to Alzheimer’s disease. These are obvious questions for follow up studies.  The data also could not answer if homocysteine itself is an important cause of brain atrophy in MCI or if it is just a marker for vitamin B levels, which are acting through some other mechanism. There is a suggestion that B12 and folate were more important than B6 in terms of a protective effect, but again the study could not answer that definitively.

Conclusion

Given what we already know, the results of this study are not surprising. B12 levels in particular tend to decrease as we age, and a large portion of the populati0n are relatively low in B12. Neuroscientists have been interested for years in homocysteine and its adverse effects on the brain. It is already fairly routine to check B vitamin levels in neurological patients, including homocysteine levels, and routinely replete them if they are low or homocysteine is elevated. This study suggests that perhaps we need to do this more aggressively. The authors also suggest that fortification in food would be a good approach.

But it must be made clear that this study says nothing about Alzheimer’s disease, which is a specific pathological disease. Reporting on this has been annoyingly misleading – I think partly because of the casual and incorrect association of AD with all dementia. I also suspect that AD makes for more eye-grabbing headlines. Homocysteine may have implications for AD (it makes sense that low B vitamin levels would exacerbate AD, even if they do not cause it), but this study simply did not look at that.

I suspect (if these results hold up under replication with larger studies) that there are subpopulations with MCI that benefit from B vitamin supplementation because of the specific mechanism of their MCI. It may be that some have B vitamin deficiency causing the MCI in the first place, or that increased vascular disease is the culprit. In this study, those with the lowest baseline homocysteine did not benefit from supplementation – so this suggests that B vitamins are not a panacea for MCI.

I do think this study justifies, in addition to further research, greater awareness among practitioners for the need to routinely check B vitamin levels and homocyteine in their older patients and to supplement as needed.

Addendum:

Other bloggers discussing this trial include Carl Heneghan. He points out that the final analysis was done on a small subset of the original subjects. The researchers explained the drop out as those willing to undergo MRI, and those displaying biological compliance – in other words, the blood tests showed they actually were taking the supplements. This introduces potential bias into the results and weakens the results. I agree with this, but his bottom line is the same as mine – this is preliminary and we need follow up with larger trials, specifically those that use clinically significant outcomes like cognitive function or progression to AD.

It has also been pointed out that the lead author has a significant conflict of interest (COI):

Dr. A. D. Smith is named as an inventor on two patents held by the University of Oxford on the use of folic acid to treat Alzheimer’s disease (US6008221; US6127370); under the University’s rules he could benefit financially if the patent is exploited.

This, of course, does not invalidate the results, but does point out the need for independent replication.