B vitamins memory benefit questioned

A recent study gave B12 (500mcg)_ and folic acidWhat it does: Critical during pregnancy for the development of a baby’s brain and nerves. Also essential for brain and nerve function. Needed for utilising… (400mcg) to people age 65 and older without memory problems, but with high homocysteineHomocysteine is an amino acid found in the blood. Elevated levels of homocysteine have been associated with narrowing and hardening of the arteries, an increased… levels above 12mcmol/l, which is a risk factor for developing dementia later in life. On testing 2 years later those on B vitamins versus placebos had a lesser decline in their memory function as measured by the MiniMentalStateExam (MMSE) but no change in other cognitive tests.

The main memory test, called MMSE, has a maximum score of 30. By the time you have a score of 24 you have a problem. MMSE score drops by 0.1 per year, on average, in older people. In this study those on the placebo started with an MMSE score of 28.2 and it dropped by 0.3 to 27.9. Those taking the B vitamins started with an MMSE score of 28.1 and it dropped by 0.1 to 28.0. So, the B vitamin group had a significant one third of the reduction in their MMSE score.

The other finding that suggests a positive effect of the B vitamins was that in those with low B12 (measured using the HoloTC test) had a significantly reduced rate of decline in episodic memory. If the study had been carried out for longer this benefit might have emerged.

This study suggests that B vitamins might slightly slow down cognitive decline but do not further improve an already good memory. As the authors of the study point out “We cannot extrapolate this to persons who already have cognitive problems.”

The problem with this study is that appears to be underpowered by virtue of either being too short in time, or selecting too ‘memory healthy’ a population, to be able to see any substantial difference in 2 years. None of the people in this study developed dementia. If it had been continued for long enough for some people to start showing signs of mild cognitive impairment then the question as to whether of not B vitamins are protective could have been answered. In another study those with high homocysteine developed mild cognitive impairment 8 years later.

What is more disconcerting is that this study, and a previous one like it (Clarke et al) are being quoted as ‘proof’ that B vitamins do nothing. For example, the BBC website states “Taking vitamin B12 and folic acid supplements does not seem to cut the risk of developing dementia” This study doesn’t even begin to address that question. Given that no-one in the study did develop dementia how on earth would you be able to compare the effects of B vitamins and placebo?

The B vitamins did also effectively lower homocysteine by 5 points, which is good news since high homocysteine is an establish risk factor for developing dementia later in life. This study certainly does not mean that B vitamins don’t slow down cognitive decline in those with memory problems. If anything, it suggests a positive effect, but one that is hard to measure after only two years and more apparent in those that start of with lower B12 status. B vitamins, in those with cognitive impairment and raised homocysteine, have consistently been shown to prevent memory decline and/or accelerated brain shrinkage.

My worry is that inadequately designed studies like these will be used to ‘bury’ the remarkably positive results that have been achieved in people with the early signs of memory loss. Such an inexpensive treatment would, of course, muddy the waters for marketing a dementia drug, which remains the holy grail for big pharma.

A fuller review of the results and their meaning, analysed by Professor David Smith from the University of Oxford, published on the AlzForum.org, is given below.

Comment by Professor David Smith

In the paper by van der Zwaluw and colleagues, there are some points to consider. First, in 8 out of 12 cognitive tests there was no cognitive decline in the placebo group over two years: there was either no change, or even an improvement, and so it is difficult to know what effect of B vitamins was expected. In four of the tests there was decline in the placebo group and in one test (MMSE) this was significantly reduced by B vitamin treatment. But the changes in the other tests were very small and the authors did not provide a power estimate of whether there were enough subjects to detect a significant effect of B vitamin treatment. It should be noted that the whole cohort was only used for MMSE and episodic memory tests. The other tests were done in a subgroup of between 721 and 759 subjects.

Thus, the authors cannot claim that they have “provided class I evidence that 2-year supplementation with B vitamins…. does not affect cognitive performance,” because there was either no cognitive decline in the placebo group, or when there was decline it was small and it is likely that the number of subjects and/or the duration of the trial would not have been sufficient to detect a treatment effect. In other words, the trial was probably underpowered. The authors themselves note other limitations of the study, in particular the lack of an intermediate testing session prevents any modelling of longitudinal change and also means that the fairly large number of drop-outs (422) cannot be included in the analysis.

The authors reported that in a post-hoc analyses the subjects with low baseline holoTC levels (a measure of B12 status) showed a beneficial effect of B vitamin treatment on episodic memory. This result is consistent with the view that this was on the whole a very healthy population mostly with a good B vitamin status and so one would not expect much effect of extra B vitamins, except in the subgroup with poorer status. The authors should have done another subgroup analysis: they should have looked at the subgroup in the cohort who did actually show cognitive decline and should have done logistic regression to see if the relative risk of cognitive decline was influenced by B vitamin treatment.

The authors correctly pointed out in their last paragraph that “we cannot extrapolate this [result] to persons who already have cognitive problems.” So readers should not assume that the results are relevant to the possible treatment of cognitive impairment. Previous studies on normal elderly, many of which were included in Clarke’s recent meta-analysis, were consistent about one thing: in the placebo groups there was little, if any, cognitive decline. This was mainly for two reasons: the groups studied were very healthy with good nutrition and so good B vitamin status on the whole; secondly, the tests used (such as MMSE) are far too insensitive for longitudinal studies. For example, MMSE declines about 0.1 point per year so you need a very long trial to show an effect. The published trials were all too short and/or underpowered in terms of number of participants. But, in those subjects that either start with poor vitamin status or that are already cognitively impaired (as in mild cognitive impairment, MCI) the story is different with most studies showing a clear benefit in either cognitive function or rate of brain shrinkage or both.

Whether or not normal people with high homocysteine who do not show any cognitive impairment will benefit from lowering homocysteine is unanswered: for that we need larger and much longer clinical trials. In the OPTIMA cohort we did observe that high homocysteine in controls increased the risk of converting to MCI but that took at least 8 years (A. Oulhaj et al., unpublished). The famous Gothenburg women’s study by Skoog and colleagues (see Zylberstein et al., 2011) showed that raised homocysteine was a strong risk factor for dementia 35 years later. More trials are needed because, if it is really true, then a lot of people will benefit from increasing B vitamin intake, especially B12. The population-attributable risk of AD due to raised homocysteine is 22% and the prevalence of raised homocysteine is about 30% (see Beydoun et al, 2014) Fundamentally, there is a difference between the slow cognitive decline of normal aging and the more rapid decline due to a disease process: homocysteine is one factor in the latter but we do not yet know if it is involved in the former.

A. David Smith, OPTIMA, University of Oxford