Bloomberg News

Path of Alzheimer’s Disease Risk Gene Tracked, Scientists Say

July 24, 2013

Scientists mapped the step-by-step actions that lead to late-onset Alzheimer’s disease, research that may offer new paths to developing treatments for the ailment.

People who carried the APOE4 gene, known to increase the risk of acquiring Alzheimer’s later in life, without having the disease, experienced changes in the expression of genes in their brains that resembled those of Alzheimer’s patients, according to a study published today in the journal Nature.

The changes in gene expression may point to early markers of the disease, and may help develop drugs for Alzheimer’s, for which there is no treatment or cure. They also bolster the idea that Alzheimer’s disease alters the brain long before patients become forgetful, said Dean Hartley, the director of scientific initiatives for the Alzheimer’s Association, an advocacy organization in Chicago. He wasn’t involved in the study.

“We do need to understand more about the mechanisms involved in Alzheimer’s disease’s initiation and progression,” Hartley said in a telephone interview, noting there haven’t been any successful clinical trials for drugs that try to alter the disease’s path. “This paper is important because it’s trying to look at what’s being affected. It may suggest targets or pathways to look for new drugs.”

The research also suggests that doctors should look to treat patients before they become forgetful, Hartley said. Studies like this one may help identify places to intervene before symptoms appear, he said.

More than 5 million people in the U.S. have Alzheimer’s, the most common form of dementia, and the number may increase to as many as 16 million by 2050, according to the Alzheimer’s Association.

Brain Activity

There has been growing interest among scientists in what happens in the brain before a patient is diagnosed with clinical Alzheimer’s. Today’s study is meant to help understand those changes at the molecular and cellular levels, Asa Abeliovich, a study author and neuroscientist at Columbia University in New York, said in a telephone interview.

The APOE4 gene increases the risk of developing late-onset Alzheimer’s, the most common form of the disease, by 3 times for those who have one copy of the gene, and 10 times in those who have two. That gene was first identified in 1991.

While APOE4 raises the risk of getting Alzheimer’s, most people with the mutation don’t develop dementia, Abeliovich said. That suggests some other factor may be required for Alzheimer’s to begin. The most important non-genetic risk factor for Alzheimer’s is age. Understanding how the cellular changes from APOE4 interact with other risk factors may explain why some people develop the disease while others don’t.

Gene Targets

The researchers found 215 genes worked differently in those who had APOE4. They looked most closely at two, which act on how the body processes amyloid precursor protein, which creates the characteristic Alzheimer’s protein, beta amyloid.

“There may be more going on than just amyloid, and that might be part of the reason why it’s been hard to solve this problem” of what causes the disease, as well as how to create therapies for it, Abeliovich said.

One of the two gene targets the researchers examined in detail in their paper is called SV2A. An existing drug for epilepsy, levetiracetam, silences the gene’s activity. Adding the drug to human cells with APOE4 lowered the rate of beta amyloid accumulation in lab tests. That suggests SV2A is required to turn amyloid precursor protein into beta amyloid. It may be worth examining further as an early intervention, Abeliovich said.

“This kind of an approach, in this age where we know more and more about genomes, is going to be increasingly important to understand how risk factors work, and how we should treat them,” Abeliovich said. “Particularly with Alzheimer’s.”

To contact the reporter on this story: Elizabeth Lopatto in San Francisco at elopatto@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net


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