Discoveries II

The discovery that led to the conclusion that aluminium is a cause of Alzheimer’s disease

I defended my PhD thesis in spring 1989. The period between 1985 and 1992 proved difficult for the aluminium industry with several key publications linking exposure to aluminium with both the incidence and aetiology of Alzheimer’s disease. This period culminated with a prestigious Ciba Foundation Symposium entitled ‘Aluminium in Biology and Medicine’.

This moment in recent history may have been the last time that the aluminium industry was truly on the run. Until now that is.

The industry reacted through lame ducks at both The Wellcome Trust and The University of Oxford. Frank Watt at Oxford found himself with a spanking new nuclear microscope courtesy of funding from The Wellcome Trust. I do wonder what prompted him to apply his new toy to aluminium and Alzheimer’s disease. He had no obvious connection to the subject.

Watt and his team came up with the working hypothesis that all previous research that had demonstrated the presence of aluminium in senile plaques in Alzheimer’s disease brain tissue was wrong. Watt speculated that all previous data identifying aluminium in senile plaques was aluminium that had been introduced as contamination during processing of brain tissue.

Watt’s new nuclear microscope allowed quantitative measurement of aluminium in senile plaques in brain tissue that had received minimal processing prior to analysis. Well, surprise, surprise, Watt’s group were unable to find any aluminium in senile plaques in Alzheimer’s disease brain tissue. Their results were immediately published in Nature in 1992 in what became a landmark paper. Landmark because this paper almost single-handedly quashed any future speculation of a role for aluminium in the aetiology of Alzheimer’s disease. It also successfully prevented any further funded research on aluminium and Alzheimer’s disease. To paraphrase from Don McLean’s American Pie, this was truly the day that the aluminium/Alzheimer’s disease hypothesis died.

Watt’s paper was never going to fail. Neither those charged with its peer review nor the then Editor of Nature, John Maddox (who had been excited previously to accept my paper on silicon and aluminium, see Discoveries I) asked basic questions of Watt and his co-authors. For example, what was the sensitivity of the nuclear microscope to measure aluminium? When this question was answered post publication by Watt and published in the aforementioned Ciba Foundation Symposium, it was coyly accepted that the technique’s limit of detection was 10ppm. Thus if the concentration of aluminium in a senile plaque was not significantly higher than 10ppm then the nuclear microscope would not find it. Letters to the editor of Nature pointing out this critical flaw in the published paper were completely ignored. As I said, Watt’s Nature paper was never going to fail.

My response to this aluminium industry propaganda was to go into the laboratory. I speculated that if aluminium and amyloid beta (the primary component of senile plaques) were co-located within senile plaques in Alzheimer’s disease then amyloid beta would bind aluminium and binding would cause amyloid beta to change its shape to that found in senile plaques, namely amyloid beta in a beta sheet conformation.

The shape adopted by peptides and proteins can be determined using an analytical technique called circular dichroism spectroscopy. We began by using this method to demonstrate that amyloid beta in the absence of aluminium adopted a shape known as an alpha helical conformation.

Please see Figure 1 in my published paper. The paper is open access. Just click on the pdf icon to read the paper.

However, in the presence of aluminium the alpha helical conformation of amyloid beta was abolished in favour of a beta-pleated sheet.

Please see Figure 3 of the published paper.

Wow!

As is expected where sound science with integrity is concerned we repeated this experiment several times and we were able to confirm this seminal discovery. We demonstrated unequivocally that amyloid beta binds aluminium and in doing so causes the helical form of the peptide to rearrange to form a beta sheet. This is the exact form of amyloid beta found in senile plaques in Alzheimer’s disease. The exact form of amyloid beta that earlier research, prior to Watt’s ‘research’, had shown was co-located with aluminium in senile plaques.

Our research set the precedent that amyloid beta binds aluminium and provided unequivocal evidence that it would not be unexpected to find both co-located in senile plaques in Alzheimer’s disease. We have, of course, recently provided direct evidence of the co-localisation of aluminium and amyloid beta in senile plaques in Alzheimer’s disease.

We published our research in a leading biochemistry journal, FEBS Letters, in 1993. It was very well received at the time of publication and has since been cited over 100 times. However, the power of the flawed, even fraudulent, science published in Nature remained over whelming and was all the aluminium industry required to shut down aluminium research worldwide. This truly happened.

This ‘discovery’ that amyloid beta bound aluminium was my first experimental foray into the science of aluminium and Alzheimer’s disease and eventually lead me twenty five years later to my unequivocal conclusion, 'no aluminium, no Alzheimer's disease'.

Such remains my opinion today and will remain so until sound published science demonstrates otherwise.