The Complex Role of Sleep and Sleep Medications in Alzheimer’s Disease

It is well known that changes in sleep occur with aging. It has also been reported that there are additional changes in sleep that occur specifically in people with Alzheimer’s disease (AD). In people with AD compared with age-matched people without cognitive impairments, there are differences in EEG patterns during sleep, less time in REM sleep, and more profound circadian rhythm abnormalities (delayed circadian phase and sleep instability are most common). Further, the EEG changes are affected by amyloid deposition in the brain. 

Sleep problems also affect the risk of developing AD. In meta-analyses, the relative risk (RR) for AD in people with any sleep dysfunction was 1.69 (95% CI: 1.51-1.87), and that obstructive sleep apnea (OSA) increases risk most (RR = 2.37) Insomnia increases risk for both all cause dementia (RR = 1.17) and moreso for AD (RR = 1.51). 

Of note, people with OSA also have EEG changes that correlate with the number of apnea events/hour, arousals during sleep, and blood oxygenation drops. Using high-resolution EEG, it can be seen that these changes occur in the posterior cingulate study where amyloid is likely to be deposited first in AD. 

Use of sleep medications, benzodiazepines and z-drugs, in the 4 to 20 years before AD diagnosis have higher relative risk of AD as well. Whether this reflects sleep difficulties or sleep medication affecting cognitive decline or the reverse is unknown. It is possible that cognitive changes that are clinically unnoticeable drive sleep differences and use of sleep medications, and that the need for sleep medications should increase clinical suspicion for potential AD. 

This correlation appears to be different in men vs women. An observational study of 3,656 adults, age 65 or more, found that the men (42.2% of study population) who used sleep medication were 3.6 times more at risk for AD (HR = 3.604; P =.0001). In contrast, for the women in this study, risk varied according to whether or not the woman said she had a sleep disorder. Women who used sleep medications but did not report sleep disturbances were nearly 4 times more likely to develop AD; in contrast, women who said they had sleep disturbances and used sleep medications had a 35.2% reduced risk of AD.  

“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.  

Differences in AD risk for people using sleep medications are also different for black vs white individuals. In a study of 3,068 black and white community-dwelling adults, age 70 to 79 years and without dementia upon study enrollment were followed for 15 years. Use of sleep medications was tracked and 4.8% of participants reported using sleep medications sometimes and 5.6% reported using sleep medications often or almost always. Fewer black participants took sleep medications often or almost always than white participants (2.7% vs 7.7%, respectively. After adjusting for sociodemographic status, smoking, alcohol use, body mass index, depressive symptoms, physical activity, comorbidities, APOE4 genotype, sleep duration and disturbances, white participants who used sleep aids sometimes, often, or almost always had a 43% increased risk of AD (hazard ratio (HR) = 1.43, 95%CI 1.01-2.02) compared with those who never or rarely took sleep medications. Black participants who used sleep medications sometimes, often, or almost always had reduced risk of AD (HR = 0.84; 95% CI.38-1.83). The association did not differ by sex.

“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 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.”
 

The background information and study results in this article were presented at the Alzheimer's Association International Conference in Los Angeles, July 14-18, 2019.