Alzheimer's disease gene appears to reduce risk of developing age-related macular degeneration

FORT LAUDERDALE, Fla. -- After combining the data from three independent studies, an international group of researchers has shown that a genetic variant implicated in Alzheimer'sdisease appears to reduce by half the risk of developing age-related macular degeneration, a progressive eye disease that destroys central vision of patients over the age of 55.

Furthermore, the researchers report, a different variant of the same gene seems to significantly increase the risk for males who do not have a family history of the disease.

Specifically, the researchers compared the distribution of three variants of the apolipoprotein-E (ApoE) gene between age-related macular degeneration (AMD) patients and control subjects. Every human has one of three variants: ApoE-2, ApoE-3 or ApoE-4. The E-4 variant has been implicated in late-onset Alzheimer's disease.

"Our analysis showed that people with the E-4 variant were at half the risk of developing AMD," said Silke Schmidt, a post-doctoral fellow at Duke's Center for Human Genetics. "Then, after looking at the subgroup of patients without a family history of AMD, we found that males with the E-2 variant were at a significantly higher risk when compared to females."

Schmidt prepared the results of the teams' findings for presentation Tuesday at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). The research is supported by numerous grants from the National Eye Institute, part of the National Institutes of Health.

AMD is characterized by the slow degeneration of sight-sensing cells in the central region of the retina called the macula. As these cells degenerate, patients lose central and detail vision. It is estimated that one in six Americans between 55 and 64 have AMD; after the age of 75, one in three have the disorder.

The cause of AMD is unknown, although researchers are discovering more and more evidence that one's genetic make-up can be an important risk factor. It is also known that smoking, fatty diet and atherosclerosis are environmental risk factors, so the researchers say the likely cause of the disease is a complex interplay of both genetic and environmental factors.

"The importance of this trial is that many groups have gotten together, pooled their data, and confirmed in a large group of patients that genetic risk factors appear to be at work," said Margaret Pericak-Vance, director of the Duke University Center of Human Genetics. She and Dr. Jonathan Haines at Vanderbilt University, Michael Gorin from the University of Pittsburgh and Cornelia M. van Duijn of Erasmus University Medical School, Rotterdam, the Netherlands, are principal investigators for the study.

"When trying to tackle large and complex problems like AMD, it is essential to be able to study large groups of affected individuals," Pericak-Vance said. "The pivotal aspect of this study is that our group of researchers found a consistent result across all three different sets of data."

For its analysis, the team combined the data collected from two American studies and one European study involving a total of 524 cases of AMD and 1,187 control subjects. Of the 524 cases, 342 involved patients in which one or more additional family members had the disease (familial form) and 182 cases in which only one family member had the disease (sporadic form).

The genetic research in AMD is especially challenging since patients usually get the disease later in life, meaning that their parents have usually died. For this reason, the research typically focuses on affected sibling pairs.

After comparing all cases against controls, the researchers determined that the E-4 variant was significantly protective against the disease, and that the effect was consistent across all age groups, as well as gender. However, when the researchers looked just at the sporadic form of the disease, they found that the E-2 variant almost doubled the risks for males. The effect was absent in females.

AMD comes in two forms: the so-called "dry" form which afflicts 90 percent of sufferers and has no treatment, and the "wet" form, which can in some cases be treated by surgery. In the current study, the team found that the type of AMD had no significance in the study's outcome.

Other researchers at Duke are investigating the actual mechanisms behind how a genetic variant could lead to the disease. Researchers have known that not only is the E-4 variant linked to Alzheimer's disease, but that it is also a risk factor for developing heart disease. The ApoE gene is the blueprint for the production of a protein that helps deliver cholesterol, a critical building block of the membranes of newly forming cells. Located on the surface of circulating fat particles, ApoE normally binds to liver cells, helping them clear cholesterol from the blood.

In 1993, Duke neurologists and genetic researchers, including Pericak-Vance, presented a novel view of Alzheimer's disease when they demonstrated that the E-4 variant was a risk factor predisposing people to developing the disease -- those with the E-4 variant tended to get the disease at an earlier age.

"The fact that E-4 seems to have an opposite effect in AMD than it does in Alzheimer's disease makes it all the more fascinating," Pericak-Vance said.

Other team members included Dr. Eric Postel and Ann Saunders, from Duke; Robert Ferrell and Daniel Weeks from the University of Pittsburgh; and Caroline Klaver from Erasmus University Medical School.

Note to editors: Margaret Pericak-Vance, Ph.D., can be reached at (919) 684-2063 or [email protected]