Genetic test for Alzheimer's divides experts

Posted: March 11, 2008

Two to four of every 100 people unknowingly carry a combination of genes that renders them unusually vulnerable to Alzheimer's disease as early as their 60s.

If you want to find out whether you're one of them, the Philadelphia company Smart Genetics is about to offer a test you can order over the Web. For $399, customers receive a kit and send back a saliva sample. Within three weeks they learn whether they carry one or two copies of an Alzheimer's-associated genetic variant known as APOE4.

But while the company's chief executive officer expects to launch the test this month, some geneticists and Alzheimer's researchers question its value. They argue that those test results can do nothing to stave off the fatal disease, which robs people of memory and mental abilities.

Others say information is power, and see a rising demand for genetic testing - whether or not it's recommended by doctors or vetted by government agencies.

A study announced today in the Archives of Neurology may fuel further interest because it confirmed a gravely increased risk for people whose parents both developed the disease.

The Alzheimer's test is not for everyone, said Julian Awad, Smart Genetics cofounder and CEO. But from market research, he said, he has found potential customers who want to use the results for life planning.

"They want information about how to arrange personal affairs or talk to loved ones about how they would want to be treated if they get the disease." In addition, Awad said, "a lot of people are curious."

The 34-year-old Wharton School graduate said he planned to be tested: "My grandfather passed away from Alzheimer's disease, so this strikes close to home." His partner in the venture, 30-year-old biochemist Richard Watson, said he, too, wanted to know his genetic status.

The test examines a gene called APOE (Apolipoprotein E), which comes in three relatively common forms: APOE2, APOE3 and APOE4. Everyone gets two of these, one inherited from each parent. Some carry two different forms, and some get two of the same. The most common is APOE3, and most people carry two.

Dozens of studies have shown that people carrying two copies of APOE4 face about a 50 percent chance of getting the disease, compared with a 10 to 15 percent risk for the general population.

Even more frightening is that double APOE4 carriers get the disease earlier. According to data published by neurologist Robert Green of Boston University, those who have a first-degree family member with Alzheimer's and two APOE4s face a 40-45 percent risk of getting the disease before they reach 70.

"The effect of APOE is really on the age of onset," said neurologist Norman Relkin of New York Presbyterian Hospital. "If you possess one or two copies of APOE4, it makes it more likely that the disease will have an onset between 60 and 75."

While only 2 percent to 4 percent of people will test positive for two E4s, about a quarter of the population carries a single copy, along with an APOE2 or an APOE3. They face a somewhat elevated risk of Alzheimer's - around 25 percent - with women at significantly higher risk than men.

Although researchers disagree over the value of genetic testing, there's nearly universal agreement that the APOE gene has a powerful influence on risk and that studying it might lead to strategies to fight Alzheimer's, which now affects about five million Americans.

"The dream in this field is to prevent the disease," Mayo Clinic neurologist Neill Graff-Radford said. While APOE4 is the largest risk factor for Alzheimer's (several genes are already known to cause rare forms of the disease in the 30s, 40s and 50s), he said, "a lot of other genes are on the brink of being discovered."

Eventually, he said, researchers hope to identify about 20 genes to assess risk more accurately than with APOE alone. Using such an evaluation, Graff-Radford said, scientists could assemble groups of relatively high-risk individuals and start testing preventative measures.

Such trials could finally tell us whether we can fight off Alzheimer's with fish oil, or resveratrol (a compound in red wine), or antioxidant vitamins - all of which can prevent the disease in animals, he said. In the future, Alzheimer's might become at least partly preventable, like heart disease.

"From a research point of view, APOE testing is a great thing," Graff-Radford said. "But from a clinical point of view, there's no point in knowing until good prevention treatment is developed."

Other neurologists and genetic counselors echoed that sentiment. "If someone is going to put the effort into life planning, a direct-to-consumer test of APOE is not going to give them the answers they're looking for," said Beth Wood, a genetic counselor at the University of Pennsylvania.

"I don't know what value it would have," said John Trojanowski, codirector of the Center for Neurodegenerative Disease Research at Penn. "If you have two E4s, you might make sure you exercise and eat a healthy diet and so forth - but if you don't have any E4 alleles, you should still do that."

Why should this gene matter so much?

From what scientists have gathered, APOE influences the way the body processes a protein called beta amyloid, which builds up in the brains of people with Alzheimer's.

The APOE gene holds the code for another protein that appears to help clear beta amyloid from the brain. But the APOE4 variant doesn't do this job as efficiently as the other forms, allowing the damaging protein to build up as plaque deposits in the brain. Researchers are divided on whether the plaque is a cause of the disease or a symptom.

Several other companies have offered APOE tests over the years to evaluate Alzheimer's or heart-disease risk. Graceful Earth, for example, offers a $280 "Alzheimer's Test" on its Web site. The Hawaii company also sells herbal supplements and offers hair analysis for people and pets.

While Graceful Earth gives customers APOE results in the mail, Awad said Smart Genetics' customers would get theirs from a board-certified genetic counselor. Critics of direct-to-consumer testing say this is the only responsible way to address something this serious.

"That's a big plus. I feel much more charitable toward them," said Stanford University law professor Hank Greely, who chaired a working group studying the ethics of such testing. But even with genetic counseling, he said, misleading customers is a danger.

It's easy to scare people by telling them relative risk, he said. As an example, a mutation in a gene called BRCA1 gives men a 100-times increased risk of breast cancer, which sounds terrifying, but male breast cancer is so rare that the lifetime risk still adds up to less than 1 percent.

Likewise, various experts have described the risk associated with double APOE4 as 10 to 15 times greater than the risk among the overall population. But such figures are impossible to evaluate without also explaining the average risk, which rises dramatically with age.

The best way of presenting Alzheimer's risk information would be to provide cumulative risk at various ages, Greely said. How likely are you to get the disease at 50, 60 or 70? "That kind of information would make the most sense if people were seeking it for life planning," he said.

But a genetic counselor for Smart Genetics said she would give people only a lifetime risk - odds of getting the disease by 85 - unless they asked for an age breakdown.

Still, Boston University geneticist Lindsay Farrer, an adviser to Smart Genetics, said people got a psychological benefit from APOE testing. He's helping run a long-term clinical trial, called REVEAL, that's tracking hundreds of subjects who have been given results of APOE tests.

"They feel better with a higher degree of certainty," Farrer said.

He said he was initially skeptical when asked to get involved in Smart Genetics, but changed his mind when he realized the testing was inevitable.

"Let's be pragmatic. There's a clamor for people to get these tests, so let's do it in the safest, most ethical manner," he said.

"We're no longer in an era of the old paternalistic approach, where we waited for geneticists to say whether something was OK or not. . . . That era has gone by."

Contact staff writer Faye Flam

at 215-854-4977 or

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