Why Some Alzheimer’s Drugs Work Better Than Others

A team of UK scientists has uncovered new clues about how four Alzheimer’s drugs interact with the toxic protein amyloid beta—insights that could help explain why some treatments work better than others and when they are likely to be most effective.

In a study published today in Alzheimer’s & Dementia, researchers from the UK Dementia Research Institute (UK DRI) at the University of Cambridge, UCL, and the VIB-KU Leuven Center for Brain & Disease Research used highly sensitive techniques to see exactly how the drugs lecanemab, donanemab, gantenerumab, and aducanumab bind to the amyloid beta protein.

Amyloid beta is known to accumulate in the brains of people with Alzheimer’s disease, forming clumps or plaques that interfere with normal brain function. The drugs are all antibodies designed to attach to the protein and help the body clear it away—but the details of how this works haven’t been fully understood.

Using a pioneering method developed at Cambridge, the researchers were able to see how well each drug bound to different forms of the protein, from small early-stage clumps to larger plaques that form later in the disease. Lecanemab stood out for its strong ability to bind to small, soluble aggregates of amyloid beta—suggesting it’s best suited for use in the early stages of Alzheimer’s.

“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,” explained Emre Fertan, co-first author and PhD student at UK DRI, Cambridge. “From this, we can conclude that lecanemab is most effective when used at the earliest possible stage of disease.”

The study also found that lecanemab binds to more sites per aggregate than the other drugs, potentially making it more efficient at tagging the toxic proteins for removal. By contrast, aducanumab and gantenerumab showed a preference for binding to larger aggregates. Donanemab showed little to no binding to the smaller forms, suggesting it targets the more established plaques instead.

These findings help explain why clinical trials have produced mixed results for these drugs. Lecanemab and donanemab, both approved by the UK’s MHRA in 2024, have shown promise in slowing cognitive decline by around 30%, but neither is yet available on the NHS. Aducanumab, initially approved in the US in 2021, was withdrawn in 2024 due to limited effectiveness, while gantenerumab failed in late-stage trials and is now being reformulated under the name trontinemab.

“Until now, we haven’t really understood exactly how anti-amyloid drugs work, or why some have been more successful than others in testing and clinical trials,” said Professor Sir David Klenerman, co-lead of the study. “With this research, we have been able to start to explain the differences we see when people are treated with these different Alzheimer’s drugs.”

Professor Bart De Strooper, co-leader of the study and Group Leader at the UK DRI at UCL and VIB-KU Leuven, added: “Additional work in my lab shows that lecanemab also binds well to plaques, which is important for their removal. At that level, both lecanemab and donanemab act similarly. We still need to understand which is more important—binding to plaques or to oligomers—if we want to truly understand the benefits of these drugs.”

As well as providing crucial insights into how current drugs work, the researchers hope this method can be used to test future treatments before they reach clinical trials—potentially streamlining development and improving success rates.

https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70086