A team of scientists including UCL researchers has tested four anti-amyloid Alzheimer's therapeutics to find out how the drugs bind to toxic amyloid beta protein to tackle the disease.
Using new, highly sensitive methods, the researchers detected and visualised how amyloid beta protein - a plaque that builds up in the brains of people with Alzheimer's disease - binds to lecanemab, donanemab, gantenerumab and aducanumab.
The findings, published in Alzheimer's and Dementia and led by researchers at the UK Dementia Research Institute (UK DRI) at UCL, the UK DRI at the University of Cambridge, and the VIB-KU Leuven Centre for Brain & Disease Research, show that lecanemab performs the best at binding a small, soluble form of amyloid beta, suggesting that it is most effective, when used as early as possible in the disease progression.
Amyloid beta is one of the toxic proteins that builds up in clumps or 'aggregates' in the brains of people affected by Alzheimer's. Several drugs targeting the protein have been tested in trials over recent years. These drugs are antibodies that bind to the amyloid beta and facilitate its clearance from the brain, but exactly how this occurs is not yet known.
To test the four different anti-amyloid drugs, the researchers generated model protein aggregates in the lab, and also tested real aggregates taken from the brains of people who had died with Alzheimer's.
Using a new technique pioneered at the UK DRI at the University of Cambridge, the scientists were able to visualise the size of protein aggregate each drug preferred to bind to, and how strongly each drug binds to aggregates. The highly sensitive technique allowed the researchers to detect different sizes of soluble aggregate - from larger clumps of protein, down to very small aggregates.
In Alzheimer's, a misfolded, sticky form of amyloid beta protein first groups together into small, soluble clumps called oligomers. Oligomers group together in turn to form fibrils, which then give rise to insoluble amyloid plaques. Scientists don't yet know which form of amyloid is most damaging to cells, but there is evidence to suggest the smaller, soluble oligomers may be most toxic.
The research team found that lecanemab binds strongly to a subset of small soluble aggregates that form early on in disease. They also found that lecanemab could bind at more sites per aggregate, allowing the drug to more effectively coat the toxic protein, making it more likely to be cleared.
Aducanumab and gantenerumab bind with a lower affinity to larger aggregates that form later on in the disease progression. Their results for donanemab showed no binding to the soluble aggregates, suggesting that it preferentially binds to larger insoluble aggregates known as 'plaques', which form in the spaces between nerve cells. Further studies are needed to understand the impact of the drugs against insoluble aggregates.
Moving forward, the researchers hope their technique can be harnessed to test new and emerging therapies before they are rolled out into human trials, and offer key insight into how drugs work.
Study co-leader Professor Bart De Strooper, UK DRI at UCL, said: "These are very interesting observations. Additional work in my laboratory indicated that lecanemab binds also very well to amyloid plaques and that this is crucial for amyloid plaque removal. At that level, both lecanemab and donanemab act very similarly.
"Further work is needed to understand what is most important: binding oligomeric structures or binding amyloid plaques. This is crucial to understand the benefits of the two available amyloid lowering drugs."
Aducanumab was first approved by the US Food and Drug Administration (FDA) in 2021, but was discontinued in 2024. Lecanemab and donanemab were approved by the UK's safety regulator the MHRA in 2024, but are not currently available on the NHS, amid discussion about their cost-effectiveness. In trials, both drugs were reported to slow cognitive decline by around 30%.
Testing of gantenerumab was halted in 2022 after it showed no clinical benefit in phase 3 trials. It is now being optimised and rebranded as trontinemab.
Co-first author Emre Fertan, a PhD student at the UK DRI at the University of Cambridge, said: "In this study, we analysed how four different anti-amyloid drugs interact with the toxic amyloid beta protein that builds up in the brain in Alzheimer's disease. We were interested in finding out more about the therapeutic effects of these drugs, by studying which type of aggregates they were targeting.
"We found that, of the four drugs, lecanemab was the best at binding to small, soluble aggregates - the kind found in the brains of people with early-stage Alzheimer's disease. From this, we can conclude that lecanemab is most effective when used at the earliest possible stage of disease."
