Amyloid beta is one of the toxic proteins which 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.
Using new highly sensitive methods, scientists have detected and visualised amyloid beta protein bound to anti-amyloid drugs in the lab.
They found that lecanemab performed best in binding to small oligomeric forms of the amyloid protein, suggesting a working mode for treating people in the earlier stages of Alzheimer’s. This suggests that it is best used as early as possible in the disease progression.
The study, led by a group of researchers with diverse scientific backgrounds, including neuroscientists and chemists from the UK Dementia Research Institute (UK DRI) at the University of Cambridge, the UK DRI at UCL, and the VIB-KU Leuven Center for Brain & Disease Research, reveals insight into how four different anti-amyloid drugs interact with amyloid beta protein.
Scientists say the research, published in the journal Alzheimer’s & Dementia and funded by the UK DRI, explains why the different treatments have had varying levels of success in clinical trials.
In the study, scientists compared four different anti-amyloid drugs: lecanemab, donanemab, aducanumab and gantenerumab. They generated model protein aggregates in the lab, and also tested real aggregates taken from the brains of people who had died with Alzheimer’s.
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.
Using a new technique pioneered at the UK DRI at 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.
Whereas aducanumab and gantenerumab bind with a lower affinity to larger aggregates that form later 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.
