On Jun. 11, 2025, researchers from the Wellcome Sanger Institute, Centre of Genomic Regulation (CRG) and Institute for Bioengineering of Catalonia (IBEC) announced a large-scale study that 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.

The research team 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. 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.

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. They then used machine learning, a type of artificial intelligence, 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.

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.