Sep 09 2010
B Vitamins and Dementia
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.
12 Responses to “B Vitamins and Dementia”
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So would your recommendation be for older people to take vitamin B supplements? Those with family history of Alzheimers especially?
(Getting medical advise for my dad via Dr. Novella FTW!)
I meant, advice…
Do you think there is any difference in taking b12 orally and b12 by injection?
In my case there is. I had a gastric bypass, which apparently made absorption of B12 a problem. So I take the shot.
However, my mother is experiencing mild short term memory issues. And she takes a multi plus she is on a Lot of Boost supplement which is also loaded with vitamins.
But it would very easy for me to give her a shot if it would be better way to get her supplement.
Of course, I am grasping at straws since my Mom’s case my be exactly what you are talking about. Where B vitamins are of no value except in some subset OR even though the homocyteine is improved it doesn’t translate to an actual change in cognition.
Have you seen Ben Goldacre’s tweet mentioning previous Holford connection plus methodological problems?
I added an addendum discussing the evaluation of other bloggers.
Regarding PO vs IM B12 – it depends. Some people lose their ability to absorb B12 as they age. You can figure this out by doing a special test, or you can just take oral supplement for a couple of month and if you B12 levels do not come up, switch to injections.
This can all be done through your primary medical doctor.
You think your link was to some bad reporting, Steve? Check this out:
“In fact, an at-home nutritional program, using a lot of vitamin B12 may indeed prevent and virtually eliminate AD.”
http://findarticles.com/p/articles/mi_m0ISW/is_274/ai_n16359687/#comments
I don’t have time to read the rest, but that looks like one bad article. From CBS, no less. Not the notoriously crappy Telegraph.
They really need to determine which of the ingredients are important, assuming this effect is real. All too often this is not done and people end up taking a particular product, which may be more expensive and unnecessary. There is accumulating evidence that large doses of vitamins (including things that people thought were harmless) may have some risks associated with them. If this entire effect is due to the B12, for instance, we may not need the folic acid or pyroxidine.
“You can figure this out by doing a special test, or you can just take oral supplement for a couple of month and if you B12 levels do not come up, switch to injections.”
Or you can increase the oral dose… sometimes too low a dose is used… older patients usually need higher doses. This is usually sufficient.
One day we may wake up to find that the term Alzheimer’s has been defined into a more or less meaningless term. (Funny, the last post and comments made this point about the word ‘organic’ and ‘natural’).
Hopefully posts like this will keep the term meaningful.
Thanks for trying, anyway.
The mechanism by which homocysteine is connected to Alzheimer’s disease, other dementias, end stage liver and kidney disease and vascular diseases is through nitric oxide.
http://circ.ahajournals.org/cgi/content/abstract/104/21/2569
Homocysteine inhibits the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades asymmetric dimethylarginine (ADMA). ADMA is an endogenous inhibitor of nitric oxide synthase, and is upregulated in essentially all disorders of low NO (including Alzheimer’s and vascular disorders).
There are a lot of very good articles citing the one above showing the importance of NO in disorders associated with high homocysteine. ADMA comes from recycling of proteins that have been methylated. Vitamin-B12 is a methyl donating cofactor for recycling folate and homocysteine.
One of the reasons extra folate helps with high homocysteine levels is because there is a necessary cofactor for nitric oxide synthase, BH4. BH4 is recycled via folate dependent pathways, and also in the presence of some BH4 there is cross-talk such that folate can augment the activity of NOS. With insufficient BH4 NOS becomes “uncoupled” and produces superoxide instead of NO. With high ADMA levels NOS makes superoxide instead of NO also.
http://www.jbc.org/content/280/9/7540.full
NOS becomes “uncoupled” when superoxide and NO react to form peroxynitrite and the peroxynitrite then oxidizes an essential Zinc-thiol couple.
I think the better way to deal with high homocysteine is (usually) via more nitric oxide. The folate pathway is regulated by NO also, and I don’t think the effect of folate supplementation is really the correcting of a “deficiency”, I think it is more of a pharmacological effect. Physiology is deliberately producing more homocysteine and more ADMA. I think it is better to correct the physiology upstream of those signals, The lowering of active-folate levels is a control mechanism to control down-stream pathways that depend on active folate. Active folate is a methyl-donor and it does a lot more than just regulate NO levels via BH4. DNA methylation is partially mediated through folate, and differential DNA methylation is one mechanism by which epigenetic programming occurs.
I don’t know whether this is how lead authors typically talk to the media, but I thought it was somewhat irresponsible for Dr. AD Smith to make such statements (in the article linked above) as: “It is a very simple solution: you give someone some vitamins and you protect the brain.”
And: “This is the first trial that has shown a glimmer of hope and success. It is the first one of its kind that has worked so clearly. I think it will change the whole direction of Alzheimer’s research.”
If I didn’t know any better, I would feel compelled to snap up some B vitamins and make them a part of my daily routine. Why would I need to talk to my physician? There’s this MD in the newspaper telling me that “if I had MCI I would take it.”
True, Dr Smith does caution that “The long-term effects of taking big doses of the vitamins were not known, and there was some evidence that high folic acid intake could be linked to cancer,” but I’m already halfway to the pharmacy before I’ve gotten to this sentence.
Haven’t read the full article.
I think it is important to keep in mind that the primary endpoint analyzed was whole brain atrophy. This may or may not be relevant to functional decline in patients with MCI or AD, as cognitive assessments would be needed to evaluate that endpoint. It may be that these supplements somehow result in fluid shifts in the brain tissue that mitigate the rate of atrophy without directly affecting disease pathophysiology.
A more useful imaging endpoint would be change in rate of medial temporal lobe (especially hippocampal) atrophy as that is better correlated with cognitive decline.
It is not unreasonable to infer an impact on the AD population from an MCI study, since most patients with MCI do ultimately go on to develop AD.
[...] Last month I reported on a small study that purported to show that supplementation with the B-vitamins – B12, B6 and folate, were associated in a small study with a decrease in the amount of brain atrophy over a two year period. There were some problems with this study, but it is plausible that a subset of the population, if they are functionally low in one or more of these B vitamins, may neurologically benefit from correction through supplementation. [...]