Sleep Quality, Not Quantity, Linked to Amyloid Deposition

Pauline Anderson

March 12, 2013

Low levels in the cerebrospinal fluid of βamyloid 42 (Aβ 42), which signifies the presence of amyloid plaques, are associated with poor sleep efficiency, although not sleep quantity, a new study has found.

The findings support the hypothesis that sleep–wake abnormalities are linked with amyloid deposition in the preclinical state of Alzheimer's disease (AD), said lead author Yo-El S. Ju, MD, assistant professor, neurology, Washington University School of Medicine, St. Louis, Missouri.

"The study is a first step of determining what type of relationship there is between sleep and AD," Dr. Ju told Medscape Medical News. "This was a cross-sectional study but we had to do this study first in order to then have the foundation to go the next step, which is to look at people earlier in life who may have sleep problems but don't have amyloid deposition to see if poor sleep increases the risk of amyloid deposition and subsequent AD."

Their findings were published online March 11 in JAMA Neurology.

Dr. Yo-El S. Ju

Amyloid Cutoff

The study included 142 cognitively normal research volunteers in longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. Most (n = 124) were recruited from the Adult Children Study and were aged 45 to 75 years at baseline, with 30% having a parental history of symptomatic AD. The mean age of the entire study group was 65.6 years.

For 14 days, study participants wore an actigraph, a computerized wristwatch-like device that measures activity and movement. Quantity of sleep was the total sleep time, and sleep quality was the ratio of total sleep time to time in bed, expressed as a percentage.

Each participant had to have had cerebrospinal fluid (CSF) obtained within 3 years of the actigraphy. Researchers used a cutoff of 500 pg/mL for Aβ 42, with values less than that indicating a strong likelihood of amyloid deposition. CSF Aβ 42 levels represent the earliest detectable change in AD pathology, Dr. Ju noted. In this study, 22.5% of participants had a CSF Aβ 42 level of 500 pg/mL or less.

The researchers found that participants with a low CSF Aβ 42 level had significantly worse sleep quality compared with those who had normal levels (80.4% vs 83.7%; P = .008). After correction for age, sex, and APOE4 allele carrier statues, the 2 groups still showed a significant difference in sleep efficiency (P = .04).

A secondary measure of sleep quality (wake time after sleep onset) was also significantly worse in those with a low CSF Aβ 42 level (P = .045).

There was no difference in sleep quantity, with a 95% confidence interval of group differences crossing zero (–16.0 to 19.5 minutes), although there was a nonsignificant trend toward more time in bed among participants with amyloid deposition. This might be because people who have poor quality of sleep spend more time in bed to try to make up for it, said Dr. Ju.

Participants with more amyloid deposition reported more naps per week in their sleep diary, although this finding was not statistically significant. However, the number of participants taking naps on 3 or more days per week was significantly higher in the group with amyloid deposition. Napping, said the authors, is a manifestation of sleep–wake disturbance.

The researchers also compared the worst sleepers (less than 75% sleep efficiency) with the best sleepers (more than 89% sleep efficiency) and found the former had more than a 5 times greater chance of having preclinical AD (odds ratio, 5.6; P = .06).

Sleep is probably one component of a variety of risk factors contributing to AD, said Dr. Ju.

Possible Mechanisms

Amyloid deposition may cause sleep–wake fragmentation through several mechanisms, according to the authors. Aβ aggregation may directly interfere with neuronal function in brain regions key to sleep and wake promotion. Preclinical amyloid deposition is associated with decreased physical activity, and because exercise deepens sleep, lack of physical activity may lead to worse sleep quality. Depression, a frequent and early symptom of dementia, often manifests in insomnia.

There are also mechanisms by which poor sleep may contribute to amyloid deposition. Soluble Aβ is released during physiologic synaptic activity. During wakefulness, there are increased neuronal activity and a corresponding increase in Aβ. During sleep, neuronal activity decreases, as does Aβ.

Mounting animal evidence points to such a bidirectional relationship between sleep problems and AD, added Dr. Ju. "When you take mice that are genetically modified to develop these amyloid plaques that you see in AD, and you deprive them of sleep, they develop more of these plaques. However, going the other way, as soon as the mice get the plaques, their sleep becomes abnormal, but when the plaques are removed, their sleep goes back to normal. So it seems like sleep disruptions may contribute to getting AD, but that having the amyloid plaques also leads to worse sleep."

Observational evidence also points to a relationship between sleep disorders and AD. Dr. Ju cited a study by Kristine Yaffe, MD, and colleagues that followed a large cohort of elderly women and found that those who had obstructive sleep apnea were more likely to develop dementia.

Her own research team is carrying out a study in younger people to see whether obstructive sleep apnea causes changes in the soluble form of amyloid. "We're trying to figure out a potential pathway for how sleep problems may change the soluble amyloid and perhaps that's why we see an increased chance of having the amyloid plaques."

Important Study

For a comment on the study, Medscape Medical News approached Sonia Ancoli-Israel, PhD, professor emeritus of psychiatry and medicine; director, Gillin Sleep and Chronomedicine Research Center; deputy director, Stein Institute for Research on Aging; and director of education, University of California at San Diego Sleep Medicine Center. Dr. Ancoli-Israel has worked in the field of sleep in older adults for over 30 years.

She called it a "wonderful study" and a "very interesting" and important article, especially as mild cognitive impairment and dementia become more prevalent as the population of elderly increases. "I've done a lot of research in sleep and cognition but not looking at amyloid distribution, so this really takes it down to more of the basic science level which is fascinating, and it corroborates what we have found."

Her research has shown that poor sleep puts people at greater risk for cognitive impairment. One of her studies showed that treating sleep apnea in patients with mild to moderate AD improved cognition.

Getting even 1 hour less than the required sleep (7 to 8 hours nightly) leads to problems with memory, concentration, and attention, said Dr. Ancoli-Israel.

She hopes that research such as this new study will spur physicians to pay more attention to sleep issues in older patients, who might not bring up the topic themselves. But physicians are often too busy to inquire about sleep problems or don't know how to treat them.

"Sleep is not their specialty so they don't ask," she said. "Perhaps they don't want to know because they don't know what to do short of giving a sleeping pill, which is not always the answer, especially in older adults."

Although she felt the current study highlights the connection between sleep fragmentation and amyloid deposition, she wondered why the authors didn't use objective 24-hour measurements of daytime naps available from the actigraphy data.

In response, Dr. Ju explained that the sleep diaries provided more accurate information on napping.

"On the actigraphy record, it can be hard to distinguish brief naps from times when someone is sitting still, for example, watching TV, or has taken the actigraph off to take a shower. At night, since people are getting into bed to sleep for long periods, we can usually tell these things apart."

This work was supported by National Institutes of Health (NIH) grants and the Ellison Medical Foundation Senior Scholar Award. The authors acknowledge the generous support of Fred Simmons and Olga Mohan. The publication was made possible by a grant from the National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research. Dr. Ju and Dr. Ancoli-Israel have disclosed no relevant financial relationships.

JAMA Neurol. Published online March 11, 2013. Abstract