The new gene may drive the first brain changes

Alzheimer disease

PET scan of a human brain with Alzheimer’s disease. Credit: public domain

A newly discovered Alzheimer’s gene may trigger the first appearance of amyloid plaques in the brain, according to a study led by researchers at Columbia University Irving Medical Center.

Some variants of the gene, RBFOX1, appear to increase the concentration of protein fragments that make up these plaques and may contribute to the breakdown of critical connections between neurons, another early sign of the disease.

The finding could lead to new therapies that prevent Alzheimer’s and better ways to identify people at increased risk of developing the disease.

In recent years, amyloid PET brain imaging has helped reveal that the first signs of Alzheimer’s disease (amyloid deposits in the brain) appear as early as 10 to 15 years before any symptoms of the disease manifest.

But aside from the few cases caused by rare hereditary genes, researchers have been looking for the cause of excessive amyloid accumulation in the brains of Alzheimer’s patients.

To find genes that drive AMYLOID accumulation EARLY, the new study looked at the genomes of thousands of people whose PET images revealed amyloid deposits in the brain but had not yet developed Alzheimer’s symptoms.

“By studying people with the first signs of Alzheimer’s, we can find genes that are unequivocally related to the onset of the disease. And these genes are more likely to lead to therapies that can prevent the development of the disease,” he says. Richard Mayeux, MD. president of neurology at the Vagelos College of Physicians and Surgeons at Columbia University, who led the study.

The study analyzed the genomes of nearly 4,300 people who did not have Alzheimer’s but whose brains already contained varying amounts of amyloid plaque, as measured by PET imaging using amyloid tracers.

Genetic analysis uncovered a link between the appearance of amyloid deposits and APOE, a known Alzheimer’s gene, and a new gene, RBFOX1.

About 10% of people in the study (predominantly of European descent) had RBFOX1 variants that were related to the appearance of amyloid deposits.

Lower amounts of RBFOX1 in the brain appeared to be associated with increased amyloid and global cognitive decline during life.

Discovering exactly how RBFOX1 regulates amyloid plaque could lead to ways to prevent plaque buildup. Previous research has already suggested that RBFOX1 is involved in the formation of amyloid precursors and the breakdown of synapses between neurons.

The connection between RBFOX1 and amyloid plaques can be relatively easy to disentangle, unlike the well-known connection between APOE4 and amyloid, which is still not understood after decades of research.

“I think we are going to find that these eventual disease markers are where real progress can be made against Alzheimer’s,” says Mayeux. “It will be practically impossible to change the course of the disease when symptoms appear. By then, the disease has already flourished for 10 to 15 years.”

“If we can target the genes that start amyloid, and correct those problems in some way, we could prevent the disease.”

The research appears in “Association Between Common Variants in RBFOX1, an RNA Binding Protein, and Cerebral Amyloidosis in Early and Preclinical Alzheimer’s Disease,” published June 22 in JAMA Neurology.

The molecule reduces multiple pathologies associated with Alzheimer’s disease.

More information:
Neha S. Raghavan et al, Association between common variants in RBFOX1, an RNA binding protein, and cerebral amyloidosis in early and preclinical Alzheimer’s disease, JAMA Neurology (2020). DOI: 10.1001 / jamaneurol.2020.1760

Provided by Columbia University Irving Medical Center

Citation: Alzheimer: a new gene can generate the first brain changes (2020, June 23) retrieved on June 23, 2020 from

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