Amyloid: 30 years of a breakthrough theory
By Ellen Mcintosh | Thursday 07 April 2022
We are at a crucial point in dementia research, particularly in the search for life-changing treatments. Many years of pioneering research have made this possible. Scientific progress is generally the result of the steady, incremental accumulation of evidence, but every so often a landmark discovery or innovation has a transformative impact on an area of research.
This year marks 30 years since Prof Sir John Hardy published a theory that provides a foundation for our current understanding of Alzheimer’s disease and is paving the way for treatments that could change people’s lives. His work across four decades has been pivotal to the dementia research community, and this dedication was recognised as he received a knighthood in 2022 New Year Honours.
The amyloid cascade hypothesis
Not many people will know the name Carol Jennings, but her family has helped shape Alzheimer’s research for the past 30 years.
Discovering the role of amyloid, the hallmark protein of Alzheimer’s disease, was made possible by working with families that had generations of people who experienced dementia symptoms in their 40s and 50s.
Carol Jennings and her family were part of this journey. She noticed changes in her father in his 50s as well as his sister and brother, then looking back further noticed this was a pattern in the family on her father’s side around the same age. This pattern of changes and Alzheimer’s diagnosis led to Carol writing to biologist Prof John Hardy and clinician Prof Martin Rossor.
Hardy and a team of clinicians and researchers took blood from many family members so they could look at their genetics and any differences between family members who had Alzheimer’s and those who didn’t. By studying their genes, the team identified the mutation which makes a specific gene faulty and revealed the pivotal role amyloid plays in the development of Alzheimer’s.
The mutation was to a gene called APP, which provides instructions to make the ‘amyloid precursor protein’. The amyloid plaques that form in the brain during Alzheimer’s disease are made up of fragments of this protein.
Not only did this work provide insight into a rare, inherited form of Alzheimer’s, it did also to the much more common, non-genetic form of the disease.
So, what is the amyloid cascade hypothesis?
Alzheimer’s disease is the leading cause of dementia, and amyloid plaques have been a key hallmark of the disease since it was first identified over 100 years ago.
Prof Hardy set out a theory suggesting a sequence of brain changes in the disease that begins with amyloid in our brains sticking together and building up around our brain cells. It’s thought that this starts a chain reaction of damage that stops our cells being able to communicate properly, ultimately affecting how we think, talk, move and behave.
Once amyloid starts to affect brain cells, it is thought to trigger a cascade of events, much like starting a row of falling dominoes. The brain’s immune cells become overactive and start to cause more harm than good. They signal for ongoing inflammation, which then affects other normal processes in the brain, creating a negative circle of damage. Blood flow can also be affected, and other proteins start to clump together too.
This theory helps explain the three key features seen in the brains of people with Alzheimer’s disease. Firstly, the brain itself appears smaller as brain cells die – this loss is equivalent to the weight of an orange. Secondly, there are the clumps of amyloid protein called plaques. And thirdly, there are tangles of another protein called tau which are seen within brain cells.
What impact has it had on research?
Since the amyloid cascade hypothesis, there has been a drive to understand more about Alzheimer’s and other dementias. The hypothesis is still hugely influential today, although it has been built upon, modified, and challenged by researchers over the years.
Science is a collaborative process and scientists from around the world have provided new insights which together paint a huge picture of different processes that contribute to the brain changes in Alzheimer’s. Researchers are continuing to fill in more detail of this painting, which now includes inflammatory pathways, theories about the tau protein, and blood vessel changes.
Interactions between amyloid and all these other processes are the focus of many research studies today. Prof Roxana Carare at the University of Southampton and her team are looking at the way amyloid is cleared from blood vessels and how this is different in Alzheimer’s disease. Understanding how our brain’s waste disposal system clears amyloid can help identify a way to keep this working effectively in people with Alzheimer’s too. At the University of York, Dr Steven Quinn and his team are using state-of-the-art microscopy techniques to look at how amyloid interacts with brain cells to cause disease. By using the latest and most advanced technology the scientists can look at how amyloid actually causes the damage to brain cells, which will add more detail to the existing amyloid cascade hypothesis pioneered by Sir John Hardy.
Hope for the future
Progress in our understanding of the impact of amyloid in the brain would not have been possible without Carol and her family taking part in vital dementia research. It has enabled scientists to work on ways to target this protein with new drugs. The development of anti-amyloid drugs hasn’t been straightforward. There have been really disappointing setbacks along the way, but there are late-stage clinical trials testing promising new treatments.
In June 2021 the Food and Drug Administration in the US licensed a treatment for Alzheimer’s disease called aducanumab. This drug targets the amyloid build-up in the brain and marked a new stage in the search for disease-modifying treatments. The clinical trials were not a smooth journey though, which resulted in the European Medicines Agency refusing to license the drug. The news around aducanumab would’ve evoked a range of emotions for everyone, but this shows the tipping point we are at with the search for new dementia treatments.
Currently there are 28 potential new treatments in phase 3 trials for Alzheimer’s disease. Of these, four are potential new disease-modifying treatments similar to aducanumab. To find out more about this process read our blog here, or you can contact our Dementia Research Infoline to discuss current and new treatments on the horizon.