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Alzheimer's Research Aims to Stop a Ticking Time Bomb

By Kathleen Fackelmann,
USA Today

February 1, 2004

 

 

   
Barbara McCulley will never forget the day her older sister drove down the wrong side of the highway after a routine dental appointment.

She was following behind when her sister turned the wrong way on the South Carolina highway and started to accelerate.  

"I started screaming," McCulley says now about the incident, which took place in 2000. They both got home safely, but McCulley took the car keys from her sister then and there.  

"She didn't understand," McCulley says. "She just thought I was being mean."  

Her sister had Alzheimer's. McCulley, who is now 65, cared for her sister for four years until she died of the disease at age 86 on Sept. 23, 2002 .  

Now McCulley, of Simpsonville , S.C. , lives with the fact that she, too, might get the disease. As the youngest of 10, McCulley has watched as Alzheimer's has stricken five brothers and sisters, four of whom are still battling the disease today.  

McCulley's family likely has inherited a gene or genes that put them at risk of developing Alzheimer's late in life. Not everyone in the family gets it, but some do: McCulley's dad probably died of the disease, as did several other close relatives.  

McCulley has experienced no sign of Alzheimer's, but each passing year adds to her risk: "If I'm going to get this disease it'll be in the next 10 years."  

Instead of worrying about the future, McCulley took a step that she hopes might one day push the clock back on Alzheimer's — if not for her, then for the next generation: She got her family to participate in a just-completed study of Alzheimer's, one that identified a gene that might control not just whether someone gets the disease, but when.  

That finding, which appeared in the Dec. 15 issue of Human Molecular Genetics, might one day lead to powerful new drugs that could slow the disease down — possibly forever.  

"If you could delay the onset of disease past the natural life span — that would be very powerful," says Margaret Pericak-Vance, the lead researcher on the study.  

Seeking genetic clues  

Late-onset Alzheimer's, which generally strikes past age 60, is the most common form of the disease. In the past, researchers had focused on genes that put people at risk of getting the disease. Pericak-Vance and her colleagues at Duke University in Durham , N.C. , have taken a novel approach by hunting for genes that influence the timing of when symptoms appear.  

"Why do some people get it when they're 60 and others get it when they're 80?" Pericak-Vance asks.  

To find out, the team began to comb through the genetic material isolated from blood donated from families with a history of Alzheimer's. Last year, the team had narrowed the search down to a region on chromosome 10, a stretch of DNA that contained hundreds of genes.  

Eventually, the team had whittled the number of candidate genes down to four and then finally homed in on one, a gene known as GST01, or Gusto for short.  

Their research suggested that people who had inherited one version of the Gusto gene might get Alzheimer's at the earlier end of the age spectrum, for instance in their 60s rather than much later.      

This study also suggested that the same gene influenced the age at which people developed another brain disease, Parkinson's. About 1 million Americans have Parkinson's disease, a movement disorder that causes tremors and a slow, shuffling walk.  

No one knows for sure how Gusto might influence the timing of either disease, but studies suggest this gene is involved in regulating the brain's inflammatory response. Some scientists believe that inflammation plays a role in both diseases.  

The most common form of Alzheimer's is probably caused by a mix of genetic and environmental risk factors. There's no evidence that Gusto triggers the disease itself. But one version of the gene may accelerate the silent destruction of the brain so that symptoms start at an earlier age.  

Genes like Gusto give human cells the instructions to make a specific protein. The Duke team believes this version of Gusto may somehow spur the disease on. If it does, and if researchers can figure out how it works, they might be able to fashion a drug that blocks the protein — and thus slow the progression of the disease by several years.  

And if drug designers got lucky, they might push back the clock on Alzheimer's even more — from age 80 to 90 or even 100, says William Scott, a Duke epidemiologist:  

"That might help people escape the disease altogether."  

More therapies needed  

Researchers know it takes decades for Alzheimer's to ravage the brain. If a drug could stop the disease before it destroyed large parts of the human brain, that might prevent the confusion, memory loss and behavioral problems that are hallmarks of a disease that now afflicts about 4.5 million people in the USA .  

Better therapies are urgently needed for members of the boomer generation, who are rapidly approaching the high-risk zone for Alzheimer's. The number of Americans who suffer from Alzheimer's may hit the 16 million mark by the year 2050, says Bill Thies of the Alzheimer's Association in Chicago .  

But first, scientists will have to prove that the Gusto gene actually does control the age of onset. Other researchers may find the link between Gusto and Alzheimer's doesn't hold up. "One paper doesn't mean this finding is buttoned down," says Marcelle Morrison-Bogorad, an Alzheimer's expert at the National Institute on Aging, part of the National Institutes of Health in Bethesda, Md.  

Yet many experts think the Gusto finding will pan out. "My guess is this finding is real," says Richard Mayeux, a neurologist and Alzheimer's expert at Columbia University in New York .  

If it is, and if additional research goes well, scientists might one day fashion a therapy that delays the onset of Alzheimer's by 10 years. But even a delay of a few years would be worth it for many seniors, Mayeux says.  

McCulley knows that researchers won't have a cure for Alzheimer's today or even tomorrow. But she hopes the genetic studies will uncover enough information about the disease to help the next generation.  

"I know this can't help me," she says. "But maybe it can help my children or grandchildren."

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