Researchers at Karolinska Institutet and their collaborators have identified two previously unknown forms of the protein amyloid-beta that may contribute to the development of Alzheimer's. The study, published in Nature Communications, also shows that a protein previously discovered by the researchers can counteract the formation of these harmful forms, suggesting a potential new treatment approach.
Alzheimer's disease is the most common form of dementia. One protein that has long been a focus of research is amyloid-beta, which can clump together and form the plaques that characterise the disease.
In the new study, researchers from Karolinska Institutet, the University of Sheffield and the University of Cambridge investigated small clusters of amyloid-beta that form before plaques develop. Using advanced microscopy and analyses of brain tissue from deceased people with Alzheimer's, as well as mouse models and cultured nerve cells, they identified two types of amyloid-beta clusters that can damage nerve cells.
Only one form develops into plaques
Although both forms can damage nerve cells, the researchers identified an important difference: only one of them appears to develop further into plaques.
"We have identified two distinct forms of amyloid-beta that are present both in the brains of people with Alzheimer's disease and in our experimental models. Our findings show that they form in different ways and may play different roles in the progression of the disease," says Jan Johansson , professor at the Department of Medicine, Huddinge , Karolinska Institutet, and one of the study's lead researchers.
The study also shows that the protein BRICHOS, previously discovered by the research group at Karolinska Institutet, can counteract the formation of harmful forms of amyloid-beta. In mouse models, treatment with BRICHOS reduced the levels of these harmful forms. It also reduced plaque formation and inflammation in the brain, while improving performance in cognitive tests.
A potential new treatment strategy for Alzheimer's
Antibody treatments targeting amyloid-beta are already used in Alzheimer's, but the researchers believe their findings suggest an alternative approach.
"Current antibody treatments for Alzheimer's have limited effects, can cause side effects and are costly. Our findings suggest an alternative approach, aimed at preventing the formation of the forms of amyloid-beta that appear to cause the damage," says Jan Johansson.
More research is needed to understand the role these newly identified forms of amyloid-beta play in the progression of Alzheimer's. The next step is to investigate how they damage nerve cells and to further develop BRICHOS as a potential treatment. Researchers at Karolinska Institutet have established the company Briccos AB, of which KI Innovations is a co-owner and partner.
The study was conducted in collaboration with the University of Sheffield, the University of Cambridge and the University of St Andrews in the UK, as well as ETH Zurich in Switzerland. The research was funded in part by the Swedish Research Council and the Swedish Brain Foundation. Any potential conflicts of interest are disclosed in the scientific paper.
Publication
"Two functionally distinct amyloid-β intermediates link aggregation pathways to pathology in Alzheimer's disease" , Agnieszka Urbanek, Alexander J. Dear, David P. Rhodes, Emma F. Garland, Hollie E. Wareing, Harry J. Baker, Willem Molenkamp, Ruixin Zhang, Gefei Chen, Axel Abelein, Simon M. Bell, Juan A. Varela, Thomas C.T. Michaels, J Robin Highley, Georg Meisl, Jan Johansson, Suman De, Nature Communications, online 9 November 2026, doi: 10.1038/s41467-026-79028-0.
