Sleep, Circadian Rhythms, and Mechanisms of Cognitive Decline in the Human Brain

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Sleep and circadian disruption, including sleep apnea, sleep fragmentation, and circadian rhythm irregularity, affect millions of Americans, and are associated with impaired cognition and Alzheimer’s disease (AD). Challenges in applying standard techniques (e.g. polysomnography) in ambulatory settings to quantify sleep and circadian disruption in large numbers of community-dwelling older adults, and in obtaining detailed cognitive assessments and brain tissue from the same individuals, have left knowledge gaps. Thus, although sleep and circadian rhythm disruption affect millions of older Americans, there are few data concerning the contribution of their different forms to the growing number of older adults with cognitive impairment and dementia, and associated brain mechanisms. This study aims to fill these gaps. The overall goal of this study is to quantify the contributions of, and identify brain mechanisms linking, sleep and circadian rhythm disruption to cognitive decline and incident AD in older adults. In compelling preliminary work, we developed and applied a new method of measuring sleep fragmentation in the community setting using actigraphy, the non-invasive continuous measurement of movement using a watch-like device. In older adults, we found that higher sleep fragmentation is associated with 1) a greater risk of incident AD, 2) more brain arteriolosclerosis and subcortical strokes at autopsy, and 3) a higher burden of AD pathology in APOE e4 carriers. However, sleep fragmentation is only one type of sleep disruption, and its impact cannot be understood without simultaneously examining the impact of common sleep disorders such as sleep apnea, which may affect up to half of older adults. To extend these findings, we propose to use a portable battery of 2 wearable devices measuring continuous peripheral arterial tonometry, oximetry, and actigraphy to simultaneously quantify 5 key forms of sleep and circadian disruption in 780 older adults in the Rush Memory and Aging Project (R01AG17911). These will include 1) sleep apnea, 2) sleep duration, 3) sleep architecture, 4) sleep fragmentation, and 5) circadian irregularity. These measurements will be combined with donated cognitive and other clinical data, as well as post-mortem histopathology and brain MRI indices from decedents, to elucidate the brain correlates of sleep and circadian disruption in community-dwelling adults, and their impact on cognitive impairment and incident AD dementia. By overcoming key translational barriers, this study will fill important gaps in our knowledge concerning the burden and brain correlates of 5 key forms of sleep and circadian disruption in old age. This offers the potential to leverage sleep and circadian interventions to decrease the growing burden of cognitive impairment and AD, and for targeted therapies to improve brain health for the millions of Americans who experience sleep or circadian rhythm dysfunction.