By Jerome Burne
Do you believe there is a new drug for Alzheimer’s just over the horizon? That there is no truth in the popular idea that B vitamins might cut your risk of getting this dreadful disease?
Well you are wrong on both counts but it’s not your fault, you’ve quite reasonably fallen for some very sophisticated marketing. Let me explain.
You will be amazed at how tiny the benefit a drug needs to have to be hailed as a breakthrough and how ruthlessly a smokescreen of shoddy trials can be used to obscure the truth about the potential benefits of B vitamins.
This is not biased ignorant pharma bashing; it’s a reasonable conclusion from what has been happening. For instance, compare the enthusiastic way a new drug is greeted, with the low key response to research showing that cheap vitamins might do the job.
Landmark new drug breakthrough
We can do this because last week a “promising” Alzheimer’s drug called Solanezumab (designed to clear the protein beta-amyloid out of the brain) was excitedly covered in the media after trials had shown that it slightly slowed memory decline in patients.
“First treatment to slow Alzheimer’s disease unveiled in landmark breakthrough,” enthused the Telegraph. Newsweek was only slightly more restrained: “New drug shows promise for early-stage Alzheimer’s.”
Alzheimer’s Research UK made it sound as if we were pretty much on the home straight: “Hugely significant…first drug actually slowing down the course of the disease …verge of a radical breakthrough.”
Contrast this with the response that greeted reports of the B vitamin breakthrough two ago. But first here’s a quick refresher on the details of that research. A pharmacology professor at Oxford ran a trial giving very high doses of B vitamins to over 200 patients with a sort of pre-Alzheimer’s condition called Mild Cognitive Impairment (MCI) in a two year, RCT (randomised controlled trial).
Stunning result for B vitamin treatment
In other words it was proper, high quality research to test the theory that lowering the amount of the amino acid homocysteine, often found in high levels in people with Alzheimer’s, could help protect their brains.
The results were stunning – a slowdown of nearly 90% in the rate of brain shrinkage in the Alzheimer-vulnerable brain regions: ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment’ and a virtual cessation of any further memory loss A further paper found an improvement in cognition [DeJager C et al, ‘Cognitive and clinical outcomes of homocysteine lowering B vitamin treatment in mild cognitive impairment: a randomized controlled trial’, Int J Geriatr Psychiatry (2011).]
This result was the first demonstration that you can actually slow down the disease process in people with pre-Alzheimer’s disease. It got some positive media coverage – I wrote about it for the Daily Mail. However Oxford University didn’t think it was even worth issuing a press release while the response of Alzheimer’s Research UK was pure Eeyore-like in it’s pessimism: ‘Previous studies looking at B vitamins have been very disappointing and we wouldn’t want to raise people’s expectations yet,’ said a spokesperson.
So how much benefit could we expect to see from the drug that was certainly raising expectations last week, even though all previous trials involving lowering amyloid plaque had been uniformly disastrous? Not much.
Improvement with drug is actually tiny
In one test, out of a possible score of 30, those on the drug scored 1 point higher than those on a placebo. In the other two tests – possible scores 90 and 56 – the difference was never more than 2. Thanks to Dr Margaret McCartney, in the BMJ, for digging up those figures.
Alzheimer’s Research UK obviously has very flexible standards when it comes to deciding whether a new treatment is probably not going to work or can be counted as a breakthrough.
What was really going on, according to one pharma-watching site, was nurturing Ely Lilly’s share price. Investors value companies based on the odds of success of the drugs. So this is not about good news for patients but slightly hopeful news for investors.
That drug companies have an eye on the bottom line isn’t news but I had optimistically assumed that the Departments of Health, the Alzheimer’s charities, or some non-commercial research body would have thought the B vitamin study promising enough to run another trial.
Scientific way is to run trials
After all, that is what the scientific approach is supposed to involve. Test a hypothesis to destruction by replicating it. Be really useful to know, for instance, if the B vitamins given to patients with MC1 who were beginning to have cognitive problems would slow down the onset of Alzheimer’s.
How naïve! Five years since the first study was published the lead author, David Smith, Professor Emeritus of Pharmacology at Oxford, has not been able to raise the funds to run a follow-up. There have been trials by other researchers to test the idea that B vitamins could slow down cognitive decline but, crucially, they have all ignored the key findings of Smith’s trial.
Instead they tested other things that vitamin might do. The people in Smiths trial had:
- been diagnosed with MCI, which meant they had begun to develop cognitive problems,
- benefitted from taking B vitamin only if they had a high level of homocysteine.
The follow up trials either gave the vitamins to healthy people or ignored their homocysteine levels or did both. Studies that chose these options found no benefit from B vitamins. So the researchers illogically concluded that Smith’s claim about B vitamin benefits couldn’t be true either.
A trial set up to fail
An example of how these trials were done can be found in the Annals of Internal Medicine. It concluded that: “Antioxidants, folic acid, and B vitamins are harmful or ineffective for chronic disease prevention,’ it announced ‘and further large prevention trials are no longer justified. They should be avoided.’
In fact it didn’t show anything of the sort. It involved giving a multivitamin tablet called Centrum Senior (B vitamin content about 1/500th of the amount used in the original Smith trial) to 6000 healthy doctors aged 65 and over for an average of 8 years and made no attempt to measure homocysteine. That’s not science, that’s a sloppy hatchet job. For a more detailed account of how useless that and another trial was see here: http://healthinsightuk.org/2014/09/07/why-we-shouldnt-believe-new-scientists-claim-that-supplements-dont-work/
But last year the process of discrediting Smith’s work was ramped up with what looked like a very authoritative meta-analysis of 11 trials of B vitamins and cognition involving a total of 22,000 people. Run by a prestigious unit in Oxford (the B vitamin Treatment Trialists Collaboration) and press released by the universityhttp://www.ox.ac.uk/news/2014-07-16-taking-b-vitamins-won%E2%80%99t-prevent-alzheimer%E2%80%99s-disease
– unlike the original study – it looked like that was the end of the idea.
The conclusion was unambiguous. ‘Our study draws a line under the debate: B vitamins don’t reduce cognitive decline as we age,’ said lead author Dr Robert Clarke. ‘Taking folic acid and vitamin B-12 is sadly not going to prevent Alzheimer’s disease.’
Same old statistical tricks get recycled
Regular readers of HealthinsightUK.org may recognise one of the names among the list of authors of the report – Professor Sir Rory Collins, the expert in meta-analyses whose statistical skills helped to make statins the most widely prescribed drugs ever.
But closer examination revealed that the Clarke study had used precisely the same trick employed in the other negative trials. It had been able to arrive at its dismissive conclusion by excluding any trials from his analysis that involved people with MCI .
It’s like giving a remedy for period pains to boys and then, when a placebo does just as well, concluding the treatment doesn’t work, instead of realising that you have been treating the wrong sub-group. What is curious is that apparently no one from the various organisation involved spotted this elementary error.
No one in the Oxford University press office and no one from the various funding bodies such as the British Heart Foundation, Cancer Research UK, the Food Standards Agency and the Department of Health. Were they all dazzled by the prestige of the authors and by the large numbers in included in the analysis? Was there an agreement to keep quiet? Any insider information would be very welcome.
B vitamins don’t help says international team
So the failure of B vitamins to slow Alzheimer’s became the new orthodoxy. Within a month the Department of Health was sending a link to the press release to an MP who had enquired about the possible benefits B vitamins might have on the brain. The accompanying letter stated: ‘an analysis by an international team lead by researchers at the university of Oxford concluded the taking B vitamins does not slow mental decline as people age nor is it likely to prevent Alzheimer’s disease.’ (personal correspondence)
Earlier this year the Smith team and two other academics responded to Clarke’s claim (copy behind a pay wall).
Some of the points were technical such as the scale used to measure cognitive decline and assumptions about the data but the key point was that you can’t use a trial that excluded anybody with cognitive problems to dismiss the findings of research that focused exclusively on people whose memory was starting to fail.
The independent academic who hadn’t been involved in the original trial - Dr Peter Gerrard of the neuroscience research centre at St George’s, University of London – firmly rejected Clarkes’ claim pointing out there was ‘first rate scientific evidence’ that B vitamins had clear biological benefits for the brain.
‘What desperately needs to be done now,’ Garrard wrote ‘is for a clinical trial to be run to see if those benefits will slow the rate patients’ progress to Alzheimer’s. Clarke’s unjustified claims are likely to make funding for that vital trial even harder to find.’
Original B vitamin trial still not re done
But still there has been no attempt to replicate the original trial – something that would have been done within months of the original research if a drug had been involved. Instead a few months ago Clarke from Oxford produced yet another negative trial, this time an RCT with 191 people, which yet again found that if you give vitamin B12 to older people whose cognitive abilities are not declining there won’t be any improvement. (American Journal of Clinical Nutrition).
It did find that giving a B12 supplement to people who were seriously deficient in the vitamin increased the amount found in their blood. No surprise there. But the cognitive function of those getting the supplement stayed the same as those getting a placebo. Clarke claimed that this showed B vitamins don’t improve the way the brain works.
Nonsense. It shows that if your brain is working OK B vitamins won’t make it work any better. But no one, certainly not Smith, has ever said it would. Like other similar trials this one has convincingly demolished a straw man. Smith’s idea could be wrong, it urgently needs testing properly, but this is precisely what Clarke and others have totally failed to do.
The government has been banging the drum for the way it has boosted funding for Alzheimer’s, ‘helping to make the UK a world leader for research on dementia,’ according to a Department of Health press release in February.
New striking results from B vitamin research
But should drugs be the only solution? How many of those providing funding and support for the Alzheimer’s charities would be content if they knew how uncritically the charity hyped new drugs while nodding through critiques of B vitamins that are totally misleading?
Meanwhile Professor Smith, far from being disheartened by the establishment’s attempts to discredit him, has continued to use data from his original trial to reveal more of what is going on in the shrinking brain and what might make a difference to patients.
Earlier this year he published another paper (needs subscription) that reported a valuable discovery. Without a healthy level of omega-3, lowering homocysteine with B vitamins had no effect on brain shrinkage. This was a potentially hugely useful finding which could make the use of B vitamins even more precise. There can’t be any ordinary people involved with Alzheimer’s who wouldn’t want it properly tested as soon as possible.
So who do you put your money on to keep your grey cells intact for a bit longer? Professor Smith or the combined expertise of the Department of Health, the Alzheimer’s charities and several other top charities that collect millions of pounds in donations every year from patients who expect them to be working in their best interests? It is very scary that Professor Smith seems the more creditable candidate.