Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease

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Project 2 Project Summary Amyloid-β (Aβ) deposition in the brain is a key early step in the development of Alzheimer disease and is followed by tauopathy, neuronal and synaptic loss, and cognitive impairment. The presence of Alzheimer disease pathology in the brain without clinical symptoms is called “preclinical” Alzheimer disease and begins to develop at least 10-15 years prior to symptom onset. Once cognitive impairment begins, there is already marked neuronal loss. Therefore, a major goal of Alzheimer disease research is to identify the transition from Aβ deposition without evidence of neuronal injury to the early stages of tauopathy when neuronal loss and then cognitive deficts begin to develop. Reliably differentiating this transition in individuals with and without cognitive impairment is critical to: 1) predict prognosis; 2) screen and monitor response of individuals in Alzheimer disease clinical trials; and 3) guide Alzheimer disease clinical trial design. Current biomarkers of Alzheimer disease pathology are either invasive (lumbar puncture) and/or expensive (amyloid PET). Based on our data in both animals and humans, we propose that changes in sleep can serve as an informative biomarker of preclinical and symptomatic Alzheimer disease. Changes in sleep associated with Alzheimer disease pathology may provide a minimally invasive way to assess the transition from preclinical to symptomatic Alzheimer disease as well as be a functional marker that is responsive to new therapies. Work in both rodents and humans strongly suggests a bidirectional relationship between sleep and Alzheimer disease: the amount and quality of sleep may regulate Aβ deposition and/or changes in sleep parameters may indicate progression of Alzheimer disease pathology. Changes in sleep mediated by Alzheimer disease may also involve the orexinergic system. Orexin is a wake-promoting neurotransmitter and orexin deficiency results in narcolepsy. Recent cross-sectional studies associated higher CSF orexin levels with mild cognitive impairment as well as moderate and severe Alzheimer disease compared to controls. These findings suggest that orexin could be used for early detection of Alzheimer disease, however the relationship of orexin to different sleep parameters, CSF Alzheimer disease biomarkers, and neuropsychological testing is unknown. In this study, we hypothesize that longitudinally measuring sleep parameters and CSF orexin in cognitively normal and mildly demented individuals will serve to detect changes in global sleep markers and the orexinergic system as markers of brain injury at the very early progression from preclinical Alzheimer disease to mildly symptomatic Alzheimer disease.