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Double-edged sword Many genetic tests may turn out to be a mixed blessing Sunday, July 02, 2000 By Byron Spice, Science Editor, Post-Gazette
Knowing you have a gene that causes an illness can be good if there are ways to prevent it or treat it. It can be a devastating if the disease has no treatment.
But what if the gene doctors were looking for gave you both kinds of answers at once?
That's the dilemma posed by a gene called apolipoprotein E4, or APOE4. This gene is known to have the biggest effect of any inherited factor on the risk of getting heart disease. It also happens to be the gene that poses the greatest risk for someone getting Alzheimer's disease.
That means a genetic test that can provide helpful information about a treatable, potentially preventable disease turns out to give a person much worse news about a devastating disease that we can't yet do anything about.
As we learn more about our genetic map, the problem posed by APOE4 probably won't be unique. Many genetic tests may have implications for more than one disease, and as geneticists become more adept at interpreting test results, these dilemmas are likely to become more common and more daunting.
A somewhat comforting fact is that APOE4 doesn't cause disease by itself -- rather, it raises the odds. As of yet, no one can predict whether someone will get either heart disease or Alzheimer's based on testing for a single gene.
APOE, in fact, is not strictly a heart disease gene or an Alzheimer's disease gene. We tend to identify genes with diseases, but their job is to produce proteins the body needs to function. APOE is a member of a family of genes called apolipoproteins that help the body deliver cholesterol and triglyceride fats to cells through the bloodstream.
Cholesterol and fats are insoluble, so before they enter the bloodstream they must be placed in packages called lipoproteins. The form called low-density lipoprotein, or LDL, is commonly referred to as "bad" cholesterol, while high-density lipoprotein, or HDL, is "good" cholesterol.
Faulty delivery
The apolipoproteins are involved in this package and come in many varieties, of which only four -- A, B, C and E -- are well understood. The APOE variety produces a protein that sits on the surface of the lipoprotein, helping to direct it to cells that need triglycerides and, once delivery is complete, helping the liver remove the cholesterol-laden lipoprotein from the blood stream.
APOE comes in three versions, E2, E3 and E4. E3 is the "normal" version that most people have. The less common E2 version is unusually efficient and people with E2 tend to have low cholesterol levels. APOE4 is just the opposite -- its protein doesn't work very well, so more cholesterol gets left behind in the bloodstream.
High cholesterol levels increase the risk of atherosclerosis, the buildup of fatty plaque in the coronary arteries that often leads to heart attacks and strokes.
The APOE version that people have accounts for about 10 to 20 percent of the variation in cholesterol levels among individuals, regardless of diet or exercise levels, said Ilyas Kamboh, a geneticist at the University of Pittsburgh Graduate School of Public Health. APOE4 increases a person's risk of cardiovascular disease by 50 percent.
But it may play an even more significant role in the risk for late-onset Alzheimer's disease, the common form of the disease that strikes people over 65. Its mechanism of action in Alzheimer's, however, is less clear than it is for heart disease.
One hypothesis involves the formation of senile plaques in the brain, one of the hallmarks of Alzheimer's. The core of these deposits, which are found during autopsies, consists of an insoluble form of protein called beta amyloid peptide. Kamboh said APOE4 binds readily to beta amyloid peptide, converting it from a soluble to an insoluble form.
As murky as its mechanism might be, APOE4's effect on Alzheimer's risk is far more pronounced than on heart disease. As with any other gene, all people have two copies of the E2, E3 or E4 versions of APOE, in any and all combinations. A person who has one copy of the E4 version has three times the normal risk for late-onset Alzheimer's, while a person with two copies faces a 20 times greater risk.
"This is by far the greatest risk factor for Alzheimer's disease," Kamboh said. "We cannot ignore this one."
Only part of the puzzle
But no one is quite sure what to make of it. Though APOE4 might account for half of the genetic risk for Alzheimer's, other genes are clearly involved.
"There could be five genes, but it could be 55 genes," said Dr. Stephen Snyder, who directs Alzheimer's research at the National Institute of Aging.
Researchers have identified several genes they think may cause early-onset Alzheimer's, which strikes people under 50. But APOE4 is the only one identified so far for the late-onset disease.
Several labs, including Kamboh's, are focusing their hunt for another Alzheimer's gene on a region of Chromosome 12, where genetic marker studies of families with a history of Alzheimer's suggest the gene might be. The gene might be as significant as APOE4, but as yet no one has pinpointed it, much less figured out what it does.
There are other puzzling clues. About one in four white Americans have at least one copy of APOE4, compared with half of all African-Americans. Yet whites are at far greater risk for Alzheimer's than blacks. Perhaps E4 has a weaker effect in blacks; perhaps some other gene or genes confer some protection to counteract E4 in blacks. No one is sure.
More women than men suffer from Alzheimer's, but that may simply be a "survivor effect" -- women generally live longer than men, so more live to the age when late-onset Alzheimer's occurs.
Perhaps most confounding is the fact that APOE4 is neither essential for Alzheimer's, nor does its presence make it inevitable.
Some people without APOE4 develop Alzheimer's; some people with APOE4 escape.
That means testing might help identify risks within a family known to have both APOE4 and an incidence of Alzheimer's, but it doesn't have much predictive value as a general screening tool.
"You don't get much more from it than you would from a really good clinician who just examines you and asks you questions," Snyder said. "It's not ethical to talk to folks about their likelihood to get a disease when so little is known."
With no proven way of preventing, delaying or treating Alzheimer's, many researchers suggest genetic testing would be a bad idea even if -- or particularly if -- the results had predictive power.
'Let people know'
But Matt Ridley, a noted British science writer and author of "Genome," a book published this spring, argues that doctors and geneticists may be a little too protective.
"I think there's a danger in terms of too much squeamishness," Ridley said. "Why should someone suffer the risk of an early death from heart disease for fear of learning of an increased risk of dementia in old age? Why shouldn't someone at risk of Alzheimer's be able to take reasonable, if unproven, steps to delay or prevent the onset by avoiding sports that often result in head trauma, such as boxing or soccer? Shouldn't people at risk be given the option of seeking out experimental drug regimens or other research efforts?
"What I object to is experts telling us we can't take these tests," he added.
Yet real risks are involved in testing.
Employers or insurers who gain access to the results might use them to deny employment or coverage. Family members may become alarmed about the implications for their own health. And even if a patient was only interested in heart disease risk, the legal requirements of informed consent might obligate a cardiologist to also inform the patient about Alzheimer's disease risk.
The fact that both neurologists and cardiologists have lost their initial enthusiasm for APOE testing suggests yet another problem, said Eric Juengst, a biomedical ethicist at Case Western Reserve University in Cleveland.
"It's an example of the tendency to grab onto initial findings and claims and to give them more significance than they perhaps deserve," said Juengst, who was the original director of the Human Genome Project's Ethical, Legal and Social Implications program.
Scientists will need to be careful when they create and market genetic tests to ensure that patients aren't told results that might be more alarming or more reassuring than scientifically merited.
The APOE testing controversy may be receding, but not the potential for future conflicts.
"It's not something that we should be surprised to see happen again," Juengst said.
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