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Subtleties of sight
Polymorphism in APOE gene is linked to cognitive changes in middle age
Edward R. Winstead

Hunting for car keys on a cluttered desk requires visual and cognitive skills that in some people decline with age. Individual differences in what scientists call visual attention may be due to variation in a single gene. In a study of healthy, middle-age individuals, researchers found that a version of the apolipoprotein E, or APOE, gene was associated with relatively poor performance on visual attention exams designed to pick up subtle changes in cognition.

Schematic of cued visual search task. The target was a red T in a field of uppercase letters (T, N, G) colored green, red or blue. Other red letters were present, but there was never more than one red T target. The cue preceded the array by 500 milliseconds and appeared superimposed over the field until either the participant responded by pressing a button or 2 seconds elapsed.

The APOE gene comes in three forms—e2, e3, and e4; the e4 variant is a risk factor for Alzheimer's disease. Individuals in the study with one or two copies of the e4 variant showed slight declines in visual attention. Most of the subjects were younger than age 60 and displayed no symptoms of Alzheimer's. They have a close relative with Alzheimer's, however, and are considered at risk for developing the disease.

"The changes are subtle, but they are there," says Pamela M. Greenwood, of the Catholic University of America, in Washington, DC. The 97 subjects were grouped according to which form of APOE they have, and the testing revealed statistically significant differences among the groups. For example, individuals with either one or two copies of the e4 variant were slower to shift their attention away from false visual cues than were others.

"The important finding here is that the effects of a genetic risk factor were seen in fairly young individuals who show no obvious signs of the disease," says Raja Parasuraman, who directs the Cognitive Science Laboratory at the Catholic University of America. A goal of his laboratory is to characterize the biological precursors of Alzheimer's disease.

The experiment marks the end of the first stage of a long-term study established to identify cognitive changes associated with Alzheimer's that occur before clinical symptoms appear. The study volunteers were recruited with the help of Trey Sunderland, who heads the Geriatric Psychiatry Branch of the National Institute of Mental Health.

‘We are interested in the underpinnings of cognitive change’

Most Alzheimer's research has focused on memory problems. Greenwood hypothesizes that studying specific components of attention rather than the complete task may be a more effective way to detect changes linked to genes. "We are interested in the underpinnings of cognitive change and thought it would be useful to look at something that underlies memory," says Greenwood.

Forming a memory of something visual involves the processing component of visual attention. And aspects of visual attention can be evaluated with relative precision: The cognitive changes in this study occurred only in the presence of the e4 variant and were specific to two tests of visual attention. No decline was detected in a third test of visual attention, memory or general cognition.

The result surprised the researchers. "When we started the study two or three years ago, we did not expect to see effects in the first study," says Raja Parasuraman. Adds Greenwood, "It was a gamble to look for changes in people who are in their fifties," because symptoms usually do not appear in middle age. A paper describing the research appears in the current issue of Proceedings of the National Academy of Sciences.

The 97 individuals were subjected to three tests: the vigilance test, which measures the ability to carry out a boring task without faltering, and two tests of selective attention. The vigilance test establishes a baseline of performance and demonstrates a capacity for completing more complex tasks.

One test of selective attention measures the ability to search for something that's hard to find, such as keys on a cluttered desk. In the experiment, subjects searched among a field of letters for a specific color and shape—a red T. The other test measures responsiveness to visual cues. A real-life example of this sort of cue is light reflected off the windshield of an oncoming car; pedestrians who see this light know to watch out.

Although they were surprised by the results, the researchers expected to detect cognitive changes prior to the appearance of symptoms. Autopsy studies have suggested as much. The brains of some individuals who died of unrelated causes in middle age and even earlier contain pathological evidence of Alzheimer's disease. Eric Reiman, of the University of Arizona, and colleagues have demonstrated that early evidence of Alzheimer's is detectable using positron emission tomography (PET) scans. As with the APOE study, this research has no clinical applications at present.

The researchers acknowledge that the visual decline may not be due specifically to the APOE gene. "Ultimately we'll need to follow the individuals for more then a decade to gain real confirmation," says Parasuraman. "But at present the data are very suggestive of a link between the effect and this gene."

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Greenwood, P.M. et al. Genetics and visual attention: Selective deficits in healthy adult carriers of the e4 allele of the apolipoprotein E gene. Proc Natl Acad Sci USA 97, 11661-11666 (October 10, 2000).

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