A genetic variant may drive the early formation of amyloid plaques, aggregates of misfolded proteins that form in the spaces between nerve cells, in the brain in Alzheimer's disease.
Deposits of amyloid plaques in the brain are one of the hallmarks of Alzheimer's disease. Importantly, these plaques can be detected as much as ten to 15 years before the onset of other symptoms of the disease. Identifying a specific genetic variant that might contribute to amyloid protein deposition could therefore help to identify people at a greater risk for developing the disease later in life.
'By studying people with the earliest signs of Alzheimer's, we can find genes that are unequivocally related to the start of the disease. And these genes are more likely to lead to therapies that can prevent the disease from developing', said Dr Richard Mayeux, chair of neurology at Columbia University Vagelos College of Physicians and Surgeons in New York, who led the study.
Although a small proportion of Alzheimer's disease cases are caused by specific inherited genes, the team aimed to identify more common genetic variants that might contribute to the accumulation of brain amyloid in Alzheimer's disease patients.
Dr Mayeux and his colleagues analysed the genomes of 4313 participants, each of whom had varying degrees of amyloid plaques, but no other Alzheimer's symptoms.
In the study published last week in JAMA Neurology, the team compared the level of amyloid deposits with genome sequences, finding a link between high amyloid levels and APOE – a long-known Alzheimer's gene – and specific variants RBFOX1, a gene newly identified as having an association with Alzheimer's disease.
About ten percent of the people in the study, primarily patients with European ancestry, had specific RBFOX1 variants that were associated with the emergence of amyloid deposition. Further, individuals with lower levels of RBFOX1 in the brain appeared to have increased levels of amyloid plaques and experience cognitive decline later in life.
RBFOX1 is already known to be involved in the formation of amyloid precursors and the breakdown of connections between neurons – another early warning sign of Alzheimer's disease.
The team is now hopeful that they can begin to unpick the mechanism by which RBFOX1 regulates the formation of amyloid plaques, which could offer a therapeutic target in the future.
'I think we're going to find that these markers of eventual disease are where real progress can be made against Alzheimer's', Dr Mayeux said. 'If we can target the genes that get amyloid started – and correct those problems somehow – we may be able to prevent the disease'.