A Comprehensive Atlas of Alzheimer’s Mutations

Knowing that some aggressive forms of Alzheimer’s disease are genetic and caused by mutations in the amyloid beta protein, researchers at the Institute for Bioengineering of Catalonia (IBEC) and Centre for Genomic Regulation (CGR) set out to test how different amyloid beta mutations influence the formation of amyloid beta protein aggregates. 

Published in eLife, the main result is a comprehensive atlas of the genetic mutations that contribute to plaque formation in Alzheimer’s disease. The atlas may help identify patients at high risk of the disease. 

Globally, Alzheimer’s disease affects 50 million people and is the most common cause of dementia. Despite numerous clinical trials, there is still no known cure for the disease. Understanding the underlying mechanisms of how Alzheimer’s disease develops is a key step to preventing the disease. 

Typically, Alzheimer’s disease is associated with the formation of protein aggregates in the brain, called amyloid fibrils or plaques, which are toxic to neurons. Though amyloid beta is usually a soluble protein in its native form, in Alzheimer’s disease, amyloid beta proteins stick together, forming insoluble aggregates in a chain reaction. 

The researchers at IBEC and CRG have provided a way to link amyloid beta protein mutations to patient outcomes by testing the effects of more than 14,000 genetic mutations in cell-based assays, identifying which are involved in plaque formation. The first large-scale mutation map of its kind, the researchers hope it will help identify those at risk of developing the disease. 

"Specialists can use this map proactively to interpret the effect of a mutation, so that when it is found in an individual, we already know what it means and hopefully what to do,” said Benedetta Bolognesi, junior group leader at IBEC, and one of the lead authors of the study, in a recent CGR press release. “This can help us identify early in life the people that are likely to develop the disease so they can take action to prevent this, when this is possible.”