New gene influences susceptibility to late-onset Alzheimer's disease

Jun 8 2007

A new gene that influences susceptibility to late-onset Alzheimer's disease (LOAD) has been identified by an international research team that analyzed the genomes of more than a thousand people with and without the disorder.

The researchers identified the gene, called GAB2, as one that appears to influence the risk of Alzheimer's in people with a version of a gene called APOE, which is the best established genetic risk factor for LOAD.

LOAD is expected to become an overwhelming medical problem in the next few decades as the population ages, since it afflicts about 10% of people over 65 and almost half of people over 85.

The research team from 15 institutions, led by Eric Reiman and Dietrich Stephan, published their discovery in the June 7, 2007, issue of the journal Neuron, published by Cell Press. The researchers were supported by 20 of the National Institute on Aging's Alzheimer's Disease Centers.

Although the variant version of APOE, called epsilon 4, was well known to be associated with increased Alzheimer's susceptibility, there were also hints that variants of other genes modified APOE's effects, said the researchers. However, detecting the infinitesimal genetic differences that would reveal Alzheimer's susceptibility genes has been extremely difficult because of their subtle effects.

To identify such fellow traveler genes, the research team performed comparative analyses of the entire genomes of 1,411 people who were either Alzheimer's-affected carriers of APOE epsilon 4 or unaffected controls. They searched for tiny genetic variations, called single-nucleotide polymorphisms, that would reveal other susceptibility genes in the carriers who had Alzheimer's.

The researchers identified variations in the GAB2 genes that were highly associated with cases of LOAD. Further genetic analyses of LOAD cases and nonaffected people revealed that the gene was highly expressed in neurons that are vulnerable to the pathology of Alzheimer's.

Studies of the GAB2 gene have indicated that the protein it produces controls a biochemical pathway that protects against the abnormal formation of protein tangles that kill brain cells, said the researchers. To explore the gene's role, they experimentally 'silenced' the gene in neurons, observing an increase in the form of a key protein that contributes to such tangles.

"Discovery of this novel LOAD susceptibility gene provides new opportunities to investigate LOAD pathogenesis, predisposition, treatment, and prevention," concluded the researchers.