The long-suspected link between Alzheimer’s disease and abnormalities in the way amyloid protein is processed in the brain has been confirmed at last.
Usually harmless, the amyloid protein is thought to trigger neurological damage when it is broken down and transformed into toxic fragments of beta-amyloid. Previous studies have shown that people with Alzheimer’s have reduced levels of several proteins involved in processing amyloid.
To find out whether low levels of any of these proteins could cause the production of toxic beta-amyloid, Peter St George-Hyslop at the University of Toronto in Canada and colleagues studied the DNA of 6861 people, 46 per cent of whom had Alzheimer’s (Nature Genetics, DOI: 10.1038/ng1943).
Those with the disease proved significantly more likely to have variants of the gene SORL1, which usually produces a protein that binds amyloid and transports it to an area of the cell where it can be harmlessly recycled.
To demonstrate that mutations in SORL1 could trigger the disease, the researchers treated cells in the lab to deactivate the gene. This led to a substantial increase in the production of toxic beta-amyloid. “Where SORL1 is absent or defective, it allows the amyloid to float off into other areas where it is degraded,” says St George-Hyslop.
The team have identified two regions of SORL1 they believe harbour the disease-causing mutations, but have not yet found the mutations themselves.