PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a debilitating neurological disorder, and soon will reach epidemic proportions in the context of an aging population. There is a clear need to identify persons at risk for AD pathology, so that preventative strategies can be developed and implemented. Multiple emerging lines of research demonstrate that sleep disturbance, and particularly excessive daytime sleepiness and obstructive sleep apnea (OSA), both increase the risk for AD pathology and dementia. Excessive daytime sleepiness is an important clinical phenotype of OSA, with individuals with impaired alertness – a function (and salient manifestation) of excessive sleepiness – experiencing more severe sequelae. Preliminary studies from our investigative team demonstrate that diminished daytime alertness measured by the psychomotor vigilance task (PVT) is specifically related to AD pathology and cognition, and that OSA moderates relationships between impaired alertness, AD pathology, and neurocognitive function. This project will advance this vital research area by leveraging emerging Alzheimer's disease biomarkers that can be detected in blood with the wealth of unique sleep data available in the Wisconsin Sleep Cohort (WSC) Study. The WSC has followed participants since the late 1980s, and is the only longitudinal cohort with stored biospecimens, sleep, PVT, and neurocognitive data spanning decades to elucidate the relationships of daytime alertness and OSA with AD pathology and cognitive decline. This investigation will prospectively collect additional blood specimens, PVT, and neurocognitive data in a targeted sample of 450 WSC participants who are now older aged, to address three Specific Aims with testable hypotheses supported by preliminary data. First, it will determine if impaired neurobehavioral alertness is associated with higher levels of pathological phosphorylated tau. Second, it will determine whether impaired neurobehavioral alertness is associated with more severe markers of neurodegeneration. Third, it will determine if impaired neurobehavioral alertness is associated with longitudinal cognitive trajectory. For all Aims, it is hypothesized that OSA moderates relationships between daytime alertness and AD pathology and cognitive decline. Detailed sleep and health history data available in the WSC importantly allows for many key covariates to be included in statistical models used for hypothesis testing. Addressing the Specific Aims of this application will have a sizeable impact on AD and sleep research, by linking a readily obtained objective measure of neurobehavioral alertness to longitudinal risk of AD pathology and cognitive decline. In so doing, this project will ultimately lead to improved preventative and therapeutic strategies that target sleep and alertness as modifiable risk factors for Alzheimer's disease.

PROJECT NARRATIVE Alzheimer's disease is a debilitating disorder that exerts a substantial and growing impact on public health in the context of an aging population. A sizeable body of research has demonstrated that sleep problems, particularly daytime sleepiness and obstructive sleep apnea, increase the risk of developing Alzheimer's disease pathology and dementia in later life. This project will identify specific and objective measures of diminished daytime alertness that are associated with increased risk of Alzheimer's disease pathology and cognitive decline, which will be a critical advance, allowing those at greatest risk for Alzheimer's disease to be more readily identified so targeted therapies and prevention strategies can be employed.