Amyloid, Scamyloid?

How the oligomer hypothesis of Alzheimer's disease got itself in a tangle

I began my research on Alzheimer’s disease in the early 1990s. A role for aluminium in the aetiology of the disease had yet to be ascribed to quackery. This period of common sense science did not last as I explain later. During these thirty years or so I have witnessed many false dawns in the field of Alzheimer’s research and specifically treatment. One such is now the subject of significant controversy. The specific details of this case of possible fraud have been reported elsewhere. In brief, a realignment of the Amyloid Cascade Hypothesis put oligomers of amyloid beta protein centre stage and fuelled a small revolution in Alzheimer’s disease research. A revolution that directed hundreds of millions of tax payers dollars towards research on amyloid oligomers. Indeed, a revolution that resulted in myriad clinical trials aimed at treating and preventing Alzheimer’s disease. Funding cascaded down from governments, NIH, NIA, RCUK, major charities, Wellcome, Alzheimer’s charities as well as industry, primarily large pharmaceutical companies. Many of you reading this will already appreciate that there was no happy ending to this small revolution. As I write there are no effective treatments for Alzheimer’s disease though industry continues to reap substantial rewards from the sale of completely ineffective drugs, for example Aricept. While a lack of happy ending in Alzheimer’s disease research is by no means unusual the distinct possibility that this particular mini revolution was based upon a fraud, likely scientific misconduct at a very high level, is disturbing. The jury is still out and an investigation is ongoing. However, one word of caution. Central to this controversy is criticism directed through an online platform called PubPeer. I am not providing an active link to this platform (easily searchable) as I do not wish to promote it as reputable. While the platform is used by many activists investigating possible scientific fraud it also allows anonymous content. For example, attacks on my research have been from trolls delighting under pseudonyms such as Latin names for flowers. There is no integrity in such criticisms and the same must be true for a platform that supports trolling of this ilk.

As I said the scientific fraud that may have been uncovered is disturbing but it is not novel even in the field of Alzheimer’s disease research. In 1992, Nature, published a paper that made the claim that there was no aluminium in amyloid plaques in Alzheimer’s disease brain tissue. The authors of this paper knew they had made a mistake (if we are being kind to them) as their research and novel method (funded by Wellcome), nuclear microscopy, were discussed at length at the earlier Ciba Foundation Symposium on aluminium. This discussion proved to the authors that their method was simply not sensitive enough to find aluminium in human brain tissue. However, they went ahead with their submission to Nature though without one key and very senior co-author, RJP Williams FRS, who withdrew his name from the manuscript. Nature rapidly published the paper, research that they decided had killed once and for all a role for aluminium in Alzheimer’s disease. They were correct in one respect. Unlike the oligomer research, this paper did not fuel a revolution in Alzheimer’s disease research, quite the opposite, it shut down all subsequent attempts to research a role for aluminium in the disease. Every referee of every grant application cited it as a reason to reject the grant. Of course, we did not give in and we continued to do research funded primarily through philanthropy and we proved unequivocally the presence of aluminium in senile plaques in Alzheimer's disease.

The oligomer hypothesis of Alzheimer’s disease was always dead to us. In thirty years of research on the amyloid beta protein we were never able to implicate oligomers of the protein in disease aetiology. However, if this hypothesis is the product of scientific misconduct and the propensity to spread dogma over the last twenty years then someone, some organisation must be brought to book, openly and transparently. It is not only about the dollars wasted but also scientific careers ruined and most important of all the lives that continue to be lost to this most impenetrable of diseases. It is yet another chapter in the scandal that is Alzheimer’s disease research and treatment.