Longitudinal Relationships Among Sleep, Cognition and Alzheimer's Disease Biomarkers: Discerning Causal Associations, Mediators and Susceptibility

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As the population has aged, there has been a staggering increase in the prevalence and morbidity of cognitive impairment and Alzheimer's disease (AD) related dementias (ADRD): by 2050 the number of people in the U.S. with ADRD will triple to 13.8 million, and associated health care costs will exceed $1.1 trillion annually. Combinations of genetic, lifestyle and environmental factors appear to increase risk for ADRD through age- related changes in neuronal processes that lead to progressive accumulation of amyloid-beta (Aß) and tau. While there is growing recognition that disturbed sleep and circadian disturbances may accelerate Aß accumulation and cognitive decline, the literature is inconclusive regarding the causal vs non-causal role of specific sleep disturbances and has not addressed whether nocturnal hypertension (a modifiable target) mediates sleep-related cognitive outcomes. We will exploit the marked inter-individual variability in many sleep measures, as well as substantial intra-individual changes over time to develop a longitudinal framework to better approach questions of causality. We propose to leverage the comprehensive sleep phenotyping performed from 2010-2013 (MESA- SLEEP; Exam 5), along with ongoing and newly proposed data to be collected in the MESA MIND study, which includes state-of-the-art cognitive, neuropsychiatric, and brain imaging studies in a sample of MESA participants studied at 2 time points 2.5 years apart (2019-2023) to efficiently and uniquely address critical research gaps. While the MESA MIND study addresses the role of mid- and later-life vascular disease as a risk factor for ADRD, it does not address the potential contributory or mediating roles of sleep and circadian disorders. We therefore propose to efficiently expand the MESA MIND study second exam (2021-2023) to include overnight state-of-the- art polysomnography, 7-day actigraphy, and for the first time in MESA, 24-hour blood pressure recordings, aiming to recruit 1800 of the 2000 participants targeted for that exam. We will generate advanced quantitative metrics of sleep and circadian rhythm to characterize the evolution of sleep disturbances over critical aging periods. These measurements will be incorporated into longitudinal assessments of cognition in order to define the temporal associations between sleep disturbances and cognitive impairment, and thus define which sleep disturbances and metrics are antecedent factors for cognitive impairment. We will evaluate whether sleep measured 8 years prior to brain imaging, as well as trajectories of sleep change, predict neurodegeneration, cerebral vascular disease and AD brain biomarkers as measured by repeated brain MRI and PET imaging (performed as part of the MESA MIND Study). We also will assess the role of blood pressure variability and nocturnal hypertension as a mediating pathway linking sleep disturbance and cognition/AD susceptibility. We will explore differences in associations between men and women and individuals of different race/ethnic backgrounds. The study has large potential impact given that sleep disturbances and nocturnal hypertension are modifiable targets. The study also will inform gender-appropriate risk stratification approaches.