Explaining the amyloid research study controversy

A summary

• Understanding the complex mechanisms that cause the diseases of the brain that lead to dementia is absolutely crucial in developing improved diagnosis and effective treatments which can stop or slow down disease.
• One of the main theories to suggest what causes Alzheimer’s disease is called the ‘Amyloid Hypothesis’. It highlights a protein called amyloid as a major contributor to what goes wrong inside the brain in this disease.
• Recently, there have been some allegations published in the research journal Science concerning one research study investigating how amyloid protein builds up in the brains of people living with Alzheimer’s disease and forms plaques. 
• These allegations criticise a US study from 2006 that focuses on a specific type of amyloid protein called aβ*56 and its role in the causes of Alzheimer’s disease.
• It is alleged that some results from this study were falsified and now the reliability of the study has come into question. Allegations of this kind in research are taken extremely seriously in the research community but are thankfully very rare. 
• Apart from the research in question, there remains a vast amount of robust scientific evidence, which supports the view of amyloid contributing to Alzheimer’s disease.

What is amyloid?

Amyloid is a protein that is found in our brains and bodies, but in Alzheimer’s disease, amyloid sticks together and forms different sized clumps that later become plaques in the brain.

Amyloid is thought to be toxic to brain cells although which size clump causes these cells to die is still being studied. The damage to and eventual death of these brain cells is what leads to dementia.

Understanding the effects of different sized clumps of amyloid protein in the brain has been an important part of trying to understand the diseases of the brain that cause dementia. 

What are the allegations about the research study? 

In July 2022, the results of an investigation were published concerning alleged fraud in some research around a specific type of amyloid, called aβ*56. This was the name given to a specific sized clump of amyloid protein, using a measuring system which refers to the size of different molecules.

As a result, aβ*56 was thought to be one of many different types of amyloid found in the brain and was suggested to be a key contributor to the symptoms of Alzheimer’s disease.

The investigation began by looking at the initial paper that reported the discovery of aβ*56. This research paper also claimed that aβ*56 was responsible for memory and thinking problems in rats that were injected with it. 

It was found that the images in the paper that proved the existence of aβ*56 may have been manipulated. Through copying and pasting from another part of the image, it was suggested that the authors made it look like the new type of amyloid was present.

Whilst the claims made by this paper about aβ*56 contributing to Alzheimer’s disease have come into doubt, there are many other types of amyloid present within the brain that have strong evidence to support their involvement in the disease.

Sir Professor John Hardy, the principle scientist behind the ‘Amyloid Hypothesis’, stated:

‘It is unfortunate and wasteful when incorrect or, even worse, fraudulent claims are made in the scientific literature. This paper was widely cited and I am sure many groups tried to follow it up.

'I myself did not believe it and I know others, including the UK Dementia Research Institute (UK DRI) director Professor De Strooper, were also sceptical of it from the start. In the greater scheme of things, this paper has not been of importance and it will not have done too much harm to AD research.

'I am not aware of any UK researchers who have tried to follow its erroneous conclusions up here in the UK.’

What does this mean for dementia research?

This study represents a small area of amyloid research and an even smaller area of dementia research. Although these allegations are a concern, there is a huge amount of credible research evidence behind the amyloid protein’s role in the diseases which cause dementia.

It is important to remember that there are many different types of amyloid protein we know contribute to brain cell death in dementia, of which aβ*56 is only one.

We know more now than ever before about the potential causes of dementia. Research has revolutionized our understanding of what is going wrong inside the brain and has highlighted that although amyloid plays an important role in disease, it does not represent the whole picture.

Since the ‘Amyloid Hypothesis’ was first described in 1991, many additional pieces of the puzzle have been discovered and ongoing research aims to discover the complex circumstances that cause diseases like Alzheimer’s.

We now believe that it is the combination of proteins like amyloid and tau, as well as processes like inflammation and blood vessel health within the brain which drive the diseases that cause dementia.

Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, said:

'There are many types of amyloid we know contribute to brain cell death in dementia. This investigation only looked at a specific type of amyloid - aβ*56 - so if what’s suggested here ends up being true we definitely would not need to throw the baby out with the bath water.

'The amyloid hypothesis has a huge amount of credible research behind it, and has already led to three potentially promising treatments that are in the pipeline, giving us hope that we might be able to slow the progression of Alzheimer’s in the next decade.

'The 1989 ground-breaking Alzheimer’s Society funded study which led Sir Professor John Hardy to see the link between amyloid and the onset of inherited Alzheimer’s disease completely revolutionised dementia research.

'While amyloid certainly does not represent the whole story, it's crucial that we keep pushing new approaches – like tackling inflammation. It will certainly not be a one-size-fits-all drug that cures this incredibly complex group of conditions.'

What role has Alzheimer’s Society played in amyloid research?

In 1989, Alzheimer’s Society, along with the Medical Research Council, jointly funded Sir Professor John Hardy, who was investigating the causes of an inherited form of Alzheimer’s disease.

The study found that family members living with this inherited form of Alzheimer’s disease had a mutation in a gene which contains the instructions for building amyloid protein – providing the first evidence that changes in the amyloid protein contributed to inherited Alzheimer’s disease. This was the beginnings of the ‘Amyloid Hypothesis’, which has since evolved to show the complex role of amyloid in the causes of dementia. 

The ‘Amyloid Hypothesis’ has led to three treatments that are currently in accelerated pathways for the treatment of Alzheimer's disease and represent the most promising treatments that might be able to slow down progression of Alzheimer's disease.

How is research published?

When scientists make new discoveries, they publish their results as papers in peer-reviewed journals. This peer-review process occurs before the research is published and involves other experts in the field assessing the paper.

Whilst this is a very successful system, there have been rare occasions where scientists have deliberately misled the peer-reviewers by fabricating the results in their paper. This is what is claimed to have happened here and if the allegations are true is scientific fraud.

Advances in computer technology are making it easier to identify cases of false, or misleading data within research papers making modern science more trustworthy.

However, there is another step in the scientific process to test the validity of a results, which is for another scientist to repeat the experiments in a paper and get the same outcome. This repetition occurs often when research groups try to build upon published research to better understand the bigger picture.

With this study, it was suggested that other research groups had tried and failed to find aβ*56. This is an example of how scientific research is able to self-correct. 

How does Alzheimer’s Society ensure we fund the best quality research?

All research applications submitted to the Society are thoroughly assessed by an expert grant panel, which includes researchers and people affected by dementia, to ensure any study our supporters fund is of the highest calibre and relevance.