Gene Shown To Be Significant Risk Factor For Alzheimer's Disease Across Racial and Ethnic Lines

Gene Shown To Be Significant Risk Factor For Alzheimer's Disease Across Racial And Ethnic Lines Large-Scale Analysis Provides New Insights

A variant of the apolipoprotein E (apoE) gene has been shown to be a significant risk factor for Alzheimer's Disease in several ethnic and racial groups, including Caucasians, African Americans, Hispanics and Japanese. Leading a collaborative effort of hundreds of scientists around the world, researchers at Boston University School of Medicine report their conclusion in the Oct. 22 issue of JAMA. The paper, which studied the impact of the apoE gene on age and sex as well as race and ethnicity in approximately 6,000 Alzheimer's Disease patients and 8,600 non-demented controls, helps clarify the importance this gene plays in causing Alzheimer's.

According to Lindsay Farrer, PhD, professor of neurology and public health at Boston University School of Medicine, the study may shed light on the continuing debate on the merits of apoE testing for Alzheimer's Disease diagnosis. "The apoE test might be used as a tool in diagnosing Alzheimer's, but several other factors, such as ethnicity, age and sex, need to be considered in the interpretation of the apoE result," Farrer says.

ApoE is a gene which produces a protein responsible for transporting cholesterol in the bloodstream, and comes in three main varieties: 2, 3, and 4. Since everyone inherits a copy of this gene from both parents, there are six different combinations, or "genotypes," that are possible. The most common genotype is "3/3" (i.e. people who posses two copies of the apoE-3 variant), which occurs in about 65 percent of the population. The researchers sought to establish if persons with the apoE-4 or apoE-2 variants had higher or lower risks for acquiring the disease than those with the "3/3" genotype, and what role if any age, sex, and ethnicity played in the risk level.

People with the "3/4" genotype were more likely to develop Alzheimer's Disease than those with the "3/3" genotype. The "4/4" genotype was associated with the greatest risk: although they represent only 2 percent of the general Caucasion population, for instance, they make up roughly 15 percent of Alzheimer's Disease patients. The apoE-2 variant, however, appears to have a protective effect against acquiring Alzheimer's Disease: those with the "2/3" genotype were at a lower risk of acquiring the disease than those with the "3/3" genotype. (The extremely rare "2/2" genotype, which occurs only once in every 200 people, also appears to be protective.)

The data yielded some unusual patterns not found in previous studies. First, those with the "2/4" genotype were at a higher risk for Alzheimer's Disease than the general population, despite having a copy of the "protective" apoE-2 gene. "Some hypothesized that a '2/4' genotype should result in a risk level matching that of the '3/3' type, since you have one 'good' gene and one 'bad' gene. But our study demonstrates that the '2/4' genotype is deleterious," Farrer says.

Second, women possessing the "2/4" and "3/4" genotypes are at greater risk than men having the same genotypes. "This area of research has been contentious, and the data show that there are differing risk levels between the sexes," he says. In addition, age played an important role in risk. "ApoE-4 heightens the risk for Alzheimer's Disease at about age 40 and continues until age 90, although the risk diminishes roughly at age 65." The study was the first to show that apoE-4 was a significant risk factor for people between 40 and 55.

According to Farrer, more epidemiological research is needed to explore certain problems that the data revealed. "For African Americans, the pattern of association between Alzheimer's Disease and apoE-4 is less clear than with other races. So, in some sense, the jury is still out on that question," he explains. And although data on Hispanics did show that apoE-4 was associated with greater risk of the disease, the "4/4" genotype had a risk factor equal to that of the "3/4" genotype -- in contrast to the data on Caucasians and Japanese.

The study, funded in part through grants from the Alzheimer's Association, Athena Diagnostics and the National Institute on Aging, involved a special form of "meta analysis," a type of research which seeks to take small scale studies and pool them into a larger one. "Due to the nature of our collaborative effort, we had access to the raw data of all the studies that went into our investigation, which allowed us to posit original hypotheses and draw wider conclusions than more conventional meta analyses," Farrer explains.