Biomarkers associated with Alzheimer's disease increased linearly with severity of sleep-disordered breathing (SDB) in normal-weight older people, according to a study reported here.

Additionally, brain imaging of patients with SBD showed reduced metabolic activity in the composite assessment of brain areas with known vulnerability to Alzheimer's disease, reported Ricardo Osorio, MD, of New York University in New York City, and colleagues.

Lean patients with SDB also had a smaller hippocampal volume, they added.

"Sleep apnea skyrockets in the elderly, and this fact hasn't been given the attention it deserves by the sleep world or the Alzheimer's world," Osorio said in a statement. "Sleep particularly suffers from an outmoded perception that it is an inactive physiological process, when, in reality, it is a very active part of the day for the brain."

Middle-aged adults have an estimated SDB prevalence of 10% to 20%, increasing to as much as 60% among people older than 65. The explanation for the increased prevalence remains unclear, but one possibility is that SDB is an early manifestation or marker of Alzheimer's disease, according to Osorio.

Interest in the relationship of SBD to Alzheimer's disease reflects a paradigm shift in the approach to Alzheimer's research. Traditionally, research and clinical strategies have focused on the disease, but by then, little can be done to help the patient, said Osorio, noting the long list of failed clinical trials in the field.

The change in focus has led to development of multiple biomarkers for diagnosis of Alzheimer's disease at earlier stages of development. Brain imaging and laboratory tests have shown promise for early diagnosis.

"The tests that are abnormal in Alzheimer's disease also are abnormal 10 to 15 years before in normal people," Osorio said during a press briefing. "The new paradigm is to start treating patients 10 to 15 years before Alzheimer's disease is apparent."

To examine the relationship between SDB and Alzheimer's disease, investigators enrolled 68 patients, ages 64 to 87, in a prospective clinical study.

Each participant's workup consisted of a comprehensive clinical examination, neuropsychological testing, two nights of home monitoring for SDB, and at least one diagnostic procedure for Alzheimer's disease.

Normal breathing during sleep was defined as an apnea-hypopnea index (AHI) less than 5, mild SDB as an AHI of 5 to 15, and moderate to severe SDB as an AHI greater than 15. Stratification of the patients by those criteria resulted in 18 patients with normal breathing, 33 with mild SDB, and 17 with moderate-severe SDB.

The prevalence of SDB increased with body mass index (BMI), although none of the groups had a mean BMI in the obese range (greater than 30). BMI averaged 23.8 in the group with normal breathing, 25.8 in the group with mild SDB, and 29.4 in the group with moderate-severe SDB.

The group with normal breathing during sleep had a mean AHI of 2.6, increasing to 8.3 in the mild-SDB group, and 36.9 in the group with moderate-severe SDB.

Across the three groups, only lean participants (BMI less than 25 kg/m²) with SDB had laboratory or imaging results associated with Alzheimer's disease. In addition to increased CSF levels of P-Tau, the Alzheimer's disease mask (composite FDG-PET imaging score of all vulnerable brain areas) was significantly lower in lean participants with SDB, reflecting generalized glucose hypometabolism (P<0.05).

The observation that abnormal findings occurred only in lean patients added to the so-called paradox of obesity, said Osorio. Though excess weight poses a health risk in middle age, overweight or obesity appears to be protective in older people. The protective effect might involve better nutrition, less muscle atrophy, or other factors.

"A common observation in patients with Alzheimer's disease is significant weight loss," said Osorio. "Loss of muscle mass precedes memory loss in some cases."

The smaller hippocampal volume in lean patients with SBD adds to the evidence of a possible association between SBD and Alzheimer's disease, said Susheel Patil, MD, PhD, of Johns Hopkins, who moderated the press briefing.

"The issue of whether sleep apnea is a risk for Alzheimer's disease or acceleration of Alzheimer's disease would seem to have some plausibility," said Patil. "The effect could be bidirectional. Alzheimer's disease could affect the development of sleep-disordered breathing."

Osorio and colleagues have begun planning a longitudinal study to determine the direction of causality between SDB and early-stage Alzheimer's disease. The study would include an assessment of the effect of continuous positive airway pressure (CPAP) for SDB on levels of biomarkers associated with Alzheimer's disease.

"If the biomarkers change, it may indicate that SDB is causing Alzheimer's disease," Osorio said. "If they don't change, the probable conclusion is that these patients are going to develop Alzheimer's disease with or without CPAP and that Alzheimer's disease may either be causing the apnea or may simply coexist with SDB as part of aging."