Based on animal and limited human data, sleep disruption has been linked to decreased clearance and increased production of b-amyloid and tau, proteins which in their aggregated forms represent the two hallmark pathologies seen in Alzheimer?s disease. A number of different sleep parameters have also been closely tied to memory consolidation and chronic sleep disruption increases the risk of memory impairment in older individuals. However, despite data linking sleep disruption to Alzheimer?s disease pathology and memory impairment, significant gaps remain in our understanding of how sleep disruption evolves over the course of Mild Cognitive Impairment (MCI) and what aspects of sleep may be targets for intervention. In this context, we propose to directly examine the evolution of sleep disruption in relation to the in vivo progression of tau pathology, cognitive decline, and network dysfunction. Leveraging data that suggest that tau accumulation may be quite rapid during prodromal Alzheimer?s disease, we will focus these studies on individuals with MCI. We hypothesize that disrupted sleep architecture will be closely related to increased neocortical tau pathology and cognitive impairment, both cross-sectionally and longitudinally. Further, we hypothesize that sleep disruption leads to diminished connectivity in brain networks previously linked to memory performance and cognitive decline, and that this network dysregulation may partially mediate the effects of sleep disruption on cognition. Together, these studies will improve understanding on mechanistic links between sleep, cognition, and Alzheimer?s disease. More broadly, the data from these studies will critically inform the design of interventional studies modifying sleep in early Alzheimer?s disease by identifying which specific aspects of disrupted sleep are most closely tied to b-amyloid and tau pathology (potential therapeutic targets), assessing which aspects of sleep change over time in MCI, and the extent to which longitudinal polysomnography and actigraphy can measure aspects of sleep disruption relevant to Alzheimer?s disease.

Public Health Relevance

Alzheimer?s disease (AD) dementia is a devastating syndrome of progressive cognitive impairment that generates a staggering burden for patients, families, and health care systems, and for which there are no clinically-available disease-modifying treatments. Disruptions of sleep and rest-wake rhythm are potentially modifiable, increase the risk of cognitive decline, and have been associated with the increased production and reduced clearance of the two proteins thought to be most central to Alzheimer?s disease progression ? amyloid-b and tau. By combining newly-available tau PET imaging, functional MRI, neuropsychological testing, and at-home sleep measurements, we will determine if sleep disruption may act as a driver of tau protein accumulation, pathologic network activity, and cognitive decline in a population of people with Mild Cognitive Impairment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Mackiewicz, Miroslaw
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Massachusetts General Hospital
United States
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