Role of Sleep Apnea in Cognition and Alzheimer's Disease Biomarkers in WTC Responders

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Project Summary Cognitive decline is the hallmark of Alzheimer’s disease (AD) and biomarkers to measure amyloid beta (Aβ) or tau burden are increasingly being used to identify early (pre-clinical) AD risk prior to emergence of cognitive impairment. Disturbances of sleep are common in AD, mild cognitive impairment and also in normal elderly with Aβ positive biomarkers. This suggests that: i) disturbed sleep contributes to AD-neurodegeneration (i.e. sleep disturbances such as from obstructive sleep apnea (OSA) are modifiable risk factors for AD); or, ii) sleep is particularly sensitive to Aβ and neurofibrillary tangle pathology (i.e. sleep disturbance is an early biomarker of AD), impacting quality of life. Our published data show that increased OSA severity in cognitively normal older subjects is associated with increased Aβ burden. Our preliminary data also show that OSA is associated with elevated cerebrospinal fluid (CSF) tau, a finding that may have a stronger link to cognitive decline. We have recently confirmed an increased prevalence (75%) of new-onset OSA in World Trade Center (WTC) dust- exposed subjects (i.e. responders) compared to the general population. The WTC responder cohort is aging and there is evidence of early cognitive impairment and high incidence of cognitive decline compared to age matched norms. This cohort is unique for its high prevalence of OSA, the availability of longitudinal data on presence and duration of OSA as well as information on other relevant risk factors for AD such as depression and post- traumatic stress disorder (PTSD), and provides a unique opportunity to evaluate the relationship between sleep disruption, biomarkers for AD risk and cognition. The purpose of the present proposal is to examine the impact of OSA severity and sleep related changes on AD plasma biomarkers, tau burden and cognition in WTC subjects using novel methodology and adjusting for potential confounders. Aim 1 will examine longitudinal changes in plasma tau and tau burden in 64 subjects with and without OSA to test the hypothesis that OSA severity is correlated with (i) changes in plasma tau and (ii) with greater longitudinal tau burden using PET-MR imaging using 18F-PI2620. Aim 2 will examine the relationship between OSA and cognition using a visual-spatial memory test (3D-maze) and the subtle cognitive impairment test (SCIT); both tests are sensitive to sleep disruption in subjects who are cognitively normal or minimally impaired by standard neuropsychological testing. We will test the hypothesis that OSA severity at baseline predicts longitudinal decline in spatial navigational memory and SCIT. Demonstration of a relationship between OSA, AD biomarkers and cognitive impairment suggests specific risk factors for AD might be assessed non-invasively (e.g. by maze/SCIT or by finding OSA or sleep specific biomarkers). These data will guide future interventional studies targeting sleep disruption (e.g. treatment of OSA, increase sleep duration) and outcomes (e.g. improvement in cognition) with the long-term goal of improving the quality of life and health outcomes in the WTC responder cohort.