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's disease
appears to reduce by half the risk of developing agerelated
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
"Our analysis showed that people with the E-4 variant were
at half the risk of developing AMD," said Silke Schmidt, a
postdoctoral 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
"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
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 E4 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 E2 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
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 todeveloping the disease -- those
with the E-4 variant tended to get the disease at an earlier
"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.