Surprising Differences Found in How Sleep Medications Increase Dementia Risk for Some, Protect Others

LOS ANGELES, JULY 15, 2019 — New research reported at the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles evaluates drug and non-drug treatments to improve sleep patterns in persons with Alzheimer’s disease or other dementias. Sleep disruption is a common behavioral challenge that significantly reduces quality of life for people with dementia and their caregivers/family members.

“Research has shown us that not getting enough sleep because of insomnia or sleep apnea may result in problems with memory and thinking, and increase the risk for Alzheimer’s-related brain changes,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “The new findings reported at AAIC 2019 are important because disrupted sleep patterns not only put the overall health of people with dementia at further risk, they may also worsen their memory loss and disrupted thinking.”

Other studies reported at AAIC 2019 looked at the use of sleep medicines in mid-life in diverse groups and found surprising differences in their impact on later-life risk of dementia.

Sleep disturbances are common among people with Alzheimer’s and other dementias, including changes in sleep schedule and restlessness/wandering during the night. It has been reported that up to 45% of people with dementia may have sleep problems. Many people with Alzheimer’s wake up more often and stay awake longer during the night. Those who cannot sleep may wander, be unable to lie still, or yell or call out, disrupting the sleep of their caregivers. Experts estimate that in late stages of Alzheimer’s, individuals spend about 40% of their time in bed at night awake and a significant part of their daytime sleeping.

Disruption in the body's sleep-wake cycle can lead to more behavioral problems, though effective coping strategies exist. At the same time, research suggests that poor sleep habits in mid- and late-life may increase the risk for developing dementia.

New sleep-related research findings reported at AAIC 2019 include:

• More frequent use of sleep medications may be associated with higher risk of dementia, especially in older white adults compared to older black adults who experienced reduced risk. Whether the change in risk is due to the medications or sleep problems is not yet known.
• Men over 65 years of age who used sleep medications were at increased risk of developing Alzheimer’s dementia, as were some women. However, women who used sleep medications but did not have interrupted sleep had a reduced risk.
• A Phase 2 pilot study found evidence that the experimental drug lemborexant (Eisai) improved total sleep time and reduced sleep fragmentation for some persons living with mild to moderate Alzheimer’s disease dementia.
• A personalized program to reset an individual’s optimal bedtime and wake time, combined with physical activity, improved sleep quality in older adults with mild cognitive impairment.

“Research has shown us that not getting enough sleep because of insomnia or sleep apnea may result in problems with memory and thinking, and increase the risk for Alzheimer’s-related brain changes,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “The new findings reported at AAIC 2019 are important because disrupted sleep patterns not only put the overall health of people with dementia at further risk, they may also worsen their memory loss and disrupted thinking.”

Frequent Use of Sleep Medications May Increase Dementia Risk, But Differently by Race
Researchers at the University of California, San Francisco, overseen by Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology, evaluated data of 3,068 black and white (45% of women and 33% of men, African American) community-dwelling older adults age 70–79 at baseline without dementia who were enrolled in the Health, Aging and Body Composition study. The study participants were followed to see if they would develop dementia over 15 years using an algorithm that incorporates medical records, information on medication use and assessment of cognition.

A total of 147 (4.8%) participants reported taking sleep medications “sometimes”; 172 (5.6%) reported “often” or “almost always.” Thirty-four (34, 2.7%) blacks and 138 (7.7%) whites reported taking sleep medications “often” or “almost always.”

The researchers found that study participants who reported taking sleep medications “often” or “almost always” were 43% more likely to develop dementia compared to those who reported “never or rarely” taking sleep medications. Increased risk for dementia among frequent sleeping medication users was only observed among white adults in the study.

No increased risk was found for people taking sleep medications “sometimes.” There was no difference reported in men versus women.

“Based on our findings, we recommend that clinicians make more effort to be aware of their patients’ sleep problems including use of sleep aids,” said lead study author Yue Leng, PhD, University of California, San Francisco. “In particular, clinicians may need to be more cautious about prescribing sleep medications to older adults who are at high risk for dementia. There are non-pharmacological sleep treatment options that should be considered.”

Sleep Medications May Impact Dementia in Women and Men Differently
An observational study of 3,656 adults 65 and older (57.8% female) from the Cache County Study on Memory and Aging (CCSMA) evaluated if use of sleep medications was associated with an increased risk of developing Alzheimer’s, and whether risk differed between men and women.

The study found that men who reported use of sleep medication had a 3.6 times increased risk of developing Alzheimer’s disease compared to those who did not use sleep medications. In women, the risk varied by whether or not they experienced sleep disturbances. Women who used sleep medications but did not report sleep disturbances were at nearly four times greater risk for developing Alzheimer’s. Women who said they had sleep disturbances and used sleep medications were at a 35.2% reduced risk of developing Alzheimer’s.

“More research is needed to determine and understand the mechanisms underlying the differences between men and women, and the cognitive impact of using sleep medications,” said Elizabeth Vernon, MS, Utah State University, who presented the data at AAIC 2019.

Phase 2 Study Shows Potential Drug May Help Circadian Rhythms
In a four-week randomized controlled trial, lemborexant (LEM) appeared to benefit individuals with mild to moderate Alzheimer’s dementia who experience irregular sleep-wake rhythm disorder (ISWRD), a circadian rhythm sleep disorder where an individual takes numerous naps in a 24-hour period and is not able to sustain a consolidated sleep at night. LEM is currently under review with the U.S. Food and Drug Administration (FDA) as a potential drug for treatment of insomnia for adults who have difficulty falling asleep and staying asleep.

In this small Phase 2 study, 62 participants age 60 to 90 with ISWRD and mild to moderate Alzheimer’s were randomized to receive various doses of LEM (2.5 mg, 5 mg, 10 mg, 15 mg) or placebo. The study participants wore a device to track their sleep and awake times. These data were supplemented by a sleep diary completed daily by caregivers. Researchers analyzed the strength of circadian signals — the internal biological clock that regulates a person’s sleepiness and alertness, as well as daytime and nighttime activity levels, and sleep time.

The study found lower nighttime activity levels (p<0.05) for individuals in the LEM 5 mg (n=13) and LEM 15 mg (n=12) groups versus placebo (n=12). There were statistical trends toward less sleep fragmentation and higher total sleep time. No serious adverse events were reported, and cognitive function did not appear to worsen.

“We know that sleep disturbances are a significant problem for persons with Alzheimer’s disease and their caregivers,” said Margaret Moline, PhD, Eisai Inc., Woodcliff Lake, NJ. “This pilot study provides preliminary evidence that lemborexant may help improve circadian rhythms to improve sleep patterns. This may be a promising treatment for sleep problems in individuals with Alzheimer’s.”

Resetting the Biological Clock to Improve Sleep Quality
Researchers at the University of British Columbia, Vancouver, Canada conducted a 24-week randomized controlled clinical trial to examine whether improving circadian regulation by resetting the biological clock (“chronotherapy”) in older adults with mild cognitive impairment can help improve sleep quality and cognitive function.

The 96 study participants (average age 71; 57% female; n=48 per group) were randomized to either the chronotherapy intervention group or the waitlist plus education control group. The intervention included:

• four once-weekly general sleep hygiene education classes, followed by
• 20 weeks of individually-timed bright light therapy, and
• bi-weekly, individually-tailored physical activity counseling phone calls, plus
• a consumer-available physical activity tracking device.

Primary outcomes were sleep quality measured objectively using an activity monitor and subjectively with a sleep quality index (Pittsburgh Sleep Quality Index). Sleep quality was observed at baseline, 12 weeks and 24 weeks.

Participants in the intervention group significantly improved objectively measured sleep efficiency (p=0.03), sleep fragmentation (p=0.02), wake after sleep onset (p=0.04) and subjective sleep quality (p=0.03). The improvements in the intervention group were seen at 12 weeks for the objectively measured outcomes and at 24 weeks for the subjectively measured outcomes compared to the control group.

“Our results provide new evidence that a personalized behavioral medicine approach may help realign the biological clock to improve sleep quality in adults with mild cognitive impairment,” said Ryan Falck, MSc, University of British Columbia, Vancouver. “Our hope is that, by improving sleep quality, we can contribute to preventing further cognitive decline in older adults with mild cognitive impairment. More research is needed to test this possibility.”

About the Alzheimer's Association International Conference^® (AAIC^®)
The Alzheimer’s Association International Conference (AAIC) is the world’s largest gathering of researchers from around the world focused on Alzheimer’s and other dementias. As a part of the Alzheimer’s Association’s research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
AAIC 2019 home page: aaic.alz.org
AAIC 2019 newsroom: aaic.alz.org/pressroom.asp

About the Alzheimer's Association^®
The Alzheimer’s Association is the leading voluntary health organization in Alzheimer's care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. Visit alz.org or call +1 800.272.3900.

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• Yue Leng, PhD, et al. Sleep Medication Use and Risk of Dementia in a Biracial Cohort of Older Adults. (Funder(s): U.S. National Institute on Aging; Global Brain Health Institute; Global Brain Health Institute; Alzheimer’s Association; Alzheimer’s Society
• Elizabeth Vernon, MS, et al. Sex Differences in the Association between Sleep Medications and Risk of Alzheimer's Disease: The Cache County Study. (Funder(s): U.S. National Institute on Aging)
• Margaret Moline, PhD, et al. Response to Treatment with Lemborexant: Subjects with Irregular Sleep-Wake Rhythm Disorder and Alzheimer's Disease Dementia. (Funder(s): Eisai Inc., Purdue Pharma)
• Ryan Falck, MSc, et al. Improving Sleep Quality in Mild Cognitive Impairment through Chronotherapy and Physical Activity: A Randomized Controlled Trial. (Funder(s): Alzheimer Society of Canada; Vancouver Coastal Health Research Institute)

Media Contacts: 
Alzheimer’s Association Media Line, +1 312.335.4078, media@alz.org
AAIC 2019 Press Office, aaicmedia@alz.org

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