STANFORD, CALIF—The epsilon4 allele of the apolipoprotein E gene (APOE epsilon4), an established risk factor for Alzheimer’s disease (AD) and cardiovascular disease, has now also been associated with sleep-disordered breathing (SDB) in adults. Emmanuel J. Mignot, MD, PhD, and colleagues found that the odds of having SDB were about twofold higher in epsilon4-positive subjects than they were in epsilon4-negative individuals. “It may be the first genetic factor shown to be involved in sleep apnea in the general population,” said Dr. Mignot, Associate Professor in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, California.

With Stanford AD researcher Greer Murphy, Jr, MD, PhD, and colleagues, Dr. Mignot examined overnight polysomnography, serum lipid levels, and other measurements in 791 middle-aged (mean age, 49 years) participants of a longitudinal cohort study. Of these, 222 subjects (28%) possessed at least one APOE epsilon4 allele. Dr. Mignot found that the average number of apneic or hypopneic events per sleep hour (apnea-hypopnea index [AHI]) was higher in APOE epsilon4-positive subjects and increased with the number of APOE epsilon4 alleles they carried. For those with one or two epsilon4 alleles, odds ratios for having an AHI of 15 or greater were 2.1 or 3.9, respectively. “About 25% of people have at least one epsilon4 allele,” Dr. Mignot noted. Given epsilon4’s prevalence, he suggested, the allele could explain “a very significant portion of sleep apnea—conservatively, maybe 8%, but perhaps as much as 20% of the cases in the general population.”

While body mass is a factor for sleep apnea, “it’s partly genetic,” said Dr. Mignot. “Beside craniofacial features that may be determined genetically, there are probably also central nervous system problems” that contribute to SDB, he added. Daytime napping, a marker for nighttime SDB, has also been associated with AD and the epsilon4 genotype. The epsilon4 allele, which affects lipid metabolism, is also associated with ischemic cerebrovascular disease.

SDB often follows head trauma or stroke, and carriers of the epsilon4 allele recover poorly after nervous system insults, suggesting that neural damage may underlie some SDB cases. By promoting ß-amyloid plaque formation, Dr. Mignot speculated, the allele might contribute to AD-like neural damage, preferentially causing SDB in epsilon4 bearers: “As [epsilon4-positive individuals] develop more plaques in the brain, for example in respiratory centers, epsilon4 may affect the central control of breathing or muscle tone in the upper airway.” A combination of pleiotropic effects may be deadly: “There may be a very bad interaction, because apnea predisposes one for cardiovascular problems,” Dr. Mignot said, citing the idea that apnea causes sympathetic activation. Coupled with epsilon4-associated atherosclerosis, apnea could thus trigger a life-threatening cardiovascular event.

“All these people we studied were perfectly OK—they did not have AD,” Dr. Mignot pointed out. “In some cases, this apnea might be a sign of early plaque development.” As a potential marker for AD that could precede measurable cognitive changes, SDB might alert caregivers early enough to allow effective intervention, he said.

—Mimi Zucker, PhD