New Insights into Why Alzheimer's Drugs Are Effective

Researchers at University College London, in collaboration with the UK Dementia Research Institute and other international centers, have uncovered new details about how certain anti-amyloid therapies work in treating Alzheimer's disease. They investigated four different drugs—lecanemab, donanemab, gantenerumab, and aducanumab—using highly sensitive visualization techniques to understand how these antibodies bind to toxic amyloid beta proteins, which are hallmark features of Alzheimer's pathology.

Amyloid beta proteins tend to form aggregates of varying sizes, from small, soluble oligomers to larger fibrils and insoluble plaques. The study revealed that lecanemab exhibits a strong affinity for smaller, soluble aggregates that appear early in the disease process. This suggests that lecanemab may be most effective when administered early, targeting the forms of amyloid beta that are potentially most toxic to brain cells.

In contrast, drugs like aducanumab and gantenerumab mainly bind to larger, insoluble aggregates, which develop later in the disease progression. Donanemab appears to primarily target these larger plaques, which are found in the spaces between neurons. These findings help explain the varying effectiveness observed in clinical trials and underscore the importance of choosing the appropriate therapeutic window.

The researchers utilized advanced techniques, including SiMoA and dSTORM, to detect and analyze different sizes of amyloid aggregates. The ability to visualize drug-aggregate interactions at this level offers promising avenues for testing new therapies before progressing to human trials, aiding in the development of more targeted and effective treatments.

Prof. Bart De Strooper highlighted that binding to soluble oligomers might be more crucial for therapeutic success, emphasizing the need for further research to determine whether targeting oligomers or plaques yields the greatest benefit.

These insights are particularly relevant given the current regulatory and clinical landscape. For instance, lecanemab and donanemab have been approved in the UK but are not yet widely available through the NHS due to cost-effectiveness debates. Meanwhile, aducanumab was previously approved in the US but was discontinued in 2024, and gantenerumab is undergoing rebranding as trontinemab after previous trial failures.

Overall, this research advances our understanding of the mechanisms behind Alzheimer’s treatments and highlights the importance of early intervention with drugs targeting small, soluble amyloid beta aggregates.