A new large-scale study has mapped the first molecular events that drive the formation of harmful amyloid protein aggregates found in Alzheimer’s disease, pointing towards a new potential therapeutic target.
Published today (11 June) in Science Advances, researchers from the Wellcome Sanger Institute, Centre of Genomic Regulation (CRG) and Institute for Bioengineering of Catalonia1 (IBEC) used large-scale genomics and machine learning to study over 140,000 versions of a peptide called Aβ42, which forms harmful plaques in the brain and is known to play a central role in Alzheimer’s disease.
This research is a significant step towards helping scientists find new ways to prevent Alzheimer’s disease, and the methods used in the study could be applied widely to other protein reactions.
Over 55 million people are impacted by dementia globally and it is estimated that 60 to 70 per cent of these cases are Alzheimer’s disease.2 Most current treatments for Alzheimer’s do not slow or stop the disease but help manage symptoms.
Amyloid beta (Aβ) is a peptide – a short chain of amino acids. Amyloid beta peptides have a tendency to clump and aggregate, forming elongated structures known as amyloid fibrils. Over time, these fibrils accumulate into plaques which are the pathological hallmarks of more than 50 neurodegenerative diseases, and most notably play a critical central role in Alzheimer’s disease.3
For free-flowing Aβ peptides to convert into stable, structured fibrils, they require a certain amount of energy. The intermediate, short-lived state right before the peptides begin to form a fibril is known as the ‘transition state’ – it is extremely unlikely to form, which is why fibrils never form in most people.
Understanding these structures and reactions is essential to developing therapies that could treat and prevent neurodegenerative diseases. However, it is very difficult to study short-lived high energy transition states using classical methods. As such, understanding how Aβ starts aggregating remains a major challenge in Alzheimer’s research.
Therefore, in this new study researchers from the Sanger Institute, Centre of Genomic Regulation and the Institute of Bioengineering of Catalonia sought to understand how changing the genetics of Aβ affects the rate of the aggregation reaction. Specifically, the researchers looked at Aβ42 – a type of Aβ peptide with 42 amino acids commonly found in those with Alzheimer’s.
The researchers used a combination of three techniques in order to handle large amounts of information about Aβ42 at the same time. The team used massively parallel DNA synthesis to study how changing amino acids in Aβ affects the amount of energy needed to form a fibril, and genetically engineered yeast cells to measure this rate of reaction.4 They then used machine learning, a type of artificial intelligence,5 to analyse the results and generate a complete energy landscape of amyloid beta aggregation reaction, showing the effect of all possible mutations in this protein on how fast fibrils are formed.
These techniques enabled the researchers to conduct the study at a large scale and look at more than 140,000 versions of Aβ42 simultaneously. This scale has not been achieved before and helps improve the quality and accuracy of the models developed in the study.
The researchers discovered that only a few key interactions between specific parts of the amyloid protein had a strong influence on the speed of fibril formation. They found that the Aβ42 aggregation reaction begins at the end of the protein, known as the C-terminal region, one of the hydrophobic cores of the protein – the tightly packed water-repellent region of the peptide. As it is here where the peptide starts aggregating into a fibril, the researchers suggest that it is the interactions in the C-terminal region that need to be prevented to protect against and treat Alzheimer’s disease.
This is the first large-scale map of how mutations influence a protein’s behaviour in the notoriously difficult to study transition state. By identifying the interactions that drive the formation of amyloid fibrils, the team believes that preventing the formation of this transition state could pave the way for new therapeutic strategies, offering hope for future Alzheimer’s treatments. Additionally, the researchers emphasise the wide usability of their method, noting it has potential to be used across a range of proteins and diseases in future studies.
Dr Anna Arutyunyan, co-first author and Postdoctoral Fellow at the Wellcome Sanger Institute, said: “By measuring the effects of over 140,000 different versions of proteins, we have created the first comprehensive map of how individual mutations alter the energy landscape of amyloid beta aggregation – a process central to the development of Alzheimer’s disease. Our data-driven model offers the first high-resolution view of the reaction’s transition state, opening the door to more targeted strategies for therapeutic intervention."
Dr Benedetta Bolognesi, co-senior author and Group Leader at the Institute for Bioengineering of Catalonia, said: “Our study is novel for two reasons: Firstly, our “kinetic-selection” method measures how fast reactions occur — and it does so for thousands of reactions in parallel, capturing the true rate-limiting steps of the aggregation reaction. Secondly, by combining mutations, we can systematically probe the interactions between different parts of the protein as the aggregation reaction initiates. This is crucial to understand the first events in the process of protein aggregation that leads to dementia, but it also offers a powerful framework to dissect the key initiating steps of many biological reactions, not just those we’ve studied so far. I look forward to seeing all the ways in which this strategy will be employed in the future."
Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: “Dementia is the biggest health and social care issue of our time and around one million people in the UK are living with this devastating condition. This study harnesses the power of technology to fill a key piece of the puzzle in how toxic amyloid proteins accumulate in the brain and improves our understanding of how genetics influences the way this protein forms plaques. With more than 130 drugs currently being tested in Alzheimer’s disease clinical trials and an urgent need to develop more effective and safer treatments, research like this is critical to continue growing our understanding of the highly complex processes involved in Alzheimer’s disease. Our Forget Me Not Appeal runs through June, and we’re encouraging people to help fund life-changing research by donating at alzheimers.org.uk/forgetmenotappeal.”
Professor Ben Lehner, co-senior author, Head of Generative and Synthetic Genomics at the Wellcome Sanger Institute and ICREA Research Professor at the Centre for Genomic Regulation (CRG), said: “The approach we used in this study opens the door to revealing the structures of other protein transition states, including those implicated in other neurodegenerative diseases. The scale at which we analysed the amyloid peptides was unprecedented – it’s something that hasn’t been done before and we have shown it’s a powerful new method to take forward. We hope this takes us one step closer to developing treatments against Alzheimer’s disease and other neurodegenerative conditions.”
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Contact details:
Susannah Young
Press Office
Wellcome Sanger Institute
Cambridge, CB10 1SA
07907391759
Email: press.office@sanger.ac.uk
Notes to Editors:
The Institute for Bioengineering of Catalonia (IBEC) and the Centre for Genomic Regulation (CRG) are one of 42 research centres which are part of Catalonia’s research centres of excellence (CERCA). A full list of researcher affiliations can be found in the publication.
World Health Organization. Dementia. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia [Last accessed: June 2025]
C. M. Dobson (2017) The Amyloid Phenomenon and Its Links with Human Disease. Cold Spring Harb. Perspect. Biol. 9
Massively parallel sequencing (MPS), also known as next-generation sequencing (NGS), is a high-throughput method for sequencing DNA or RNA fragments in parallel. It enables sequencing millions of fragments simultaneously.
Machine learning involves using algorithms to analyse massive amounts of data from large datasets in order to identify patterns in how amino acid changes affect fibril formation and predict the energy landscape for amyloid beta aggregation.
Publication:
Anna Arutyunyan et al. (2025) ‘Massively parallel genetic perturbation suggests the energetic structure of an amyloid beta transition state.’ Science Advances. DOI: 10.1126/sciadv.adv1422
Funding:
This research is part-funded by the La Caixa Research Foundation project ‘DeepAmyloids’. A full list of funders can be found in the acknowledgements in the publication.
Selected websites:
About the Institute for Bioengineering of Catalonia - IBEC
The Institute for Bioengineering of Catalonia (IBEC) is a CERCA center, three times recognized as a Severo Ochoa Center of Excellence, and holds the TECNIO label as a technology developer and business facilitator. IBEC is a member of the Barcelona Institute of Science and Technology (BIST) and conducts multidisciplinary research at the forefront of engineering and life sciences to generate knowledge. The institute integrates fields such as nanomedicine, biophysics, biotechnology, tissue engineering, and applications of information technologies in the health sector. IBEC, established in 2005, is a collaborative effort of the Generalitat de Catalunya (Catalan Government), the University of Barcelona (UB), and the Polytechnic University of Catalonia (UPC).
About the CRG
The CRG is a biomedical research centre located in Barcelona. Created in December 2000, the CRG is home to an interdisciplinary research team of more than four hundred scientists focused on understanding the complexity of life, from the genome to the cell and a complete organism. The CRG is a research center with a unique research model, focused on recruiting internationally-recognised leaders in the field. The CRG is a member of the Barcelona Institute of Science and Technology (BIST) and is a CERCA centre, part of the research ecosystem of the Generalitat de Catalunya.
The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leader in genomics research. We apply and explore genomic technologies at scale to advance understanding of biology and improve health. Making discoveries not easily made elsewhere, our research delivers insights across health, disease, evolution and pathogen biology. We are open and collaborative; our data, results, tools, technologies and training are freely shared across the globe to advance science.
Funded by Wellcome, we have the freedom to think long-term and push the boundaries of genomics. We take on the challenges of applying our research to the real world, where we aim to bring benefit to people and society.
Find out more at www.sanger.ac.uk or follow us on Twitter, Instagram, Facebook, LinkedIn and on our Blog.
About Wellcome
Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health. https://wellcome.org/
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