PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that is poised to reach epidemic proportions given our rapidly aging population. As such, the identification of risk and resilience factors that might curb the progression of AD and delay symptom onset is a national public health imperative. Multiple emerging lines of research demonstrate that sleep disturbance, and particularly obstructive sleep apnea (OSA, a very common disorder in older adults), and poor cardiorespiratory fitness (CRF) are associated with increased risk for AD pathology and cognitive decline. Furthermore, new evidence suggests that OSA and CRF may interact in their relation to AD; however, thus far, this potential interaction is poorly understood because of the dearth of relevant data and because AD pathology is present long before detectable signs of dementia are observed. The overall objective of this project is to fill a critical gap in AD research by deploying advanced methods to estimate the age of onset of AD biomarkers in the Wisconsin Sleep Cohort (WSC), relate this emergent pathophysiology to midlife OSA and fitness, and determine how midlife OSA and fitness influence trajectories of cognitive impairment in later life. The WSC has followed adult participants since the late 1980s and is the only longitudinal cohort with objective sleep, fitness, and neurocognitive data spanning decades to explain how OSA and CRF interrelate to predict AD onset. Accordingly, by leveraging the unique sleep and health data available in the WSC Study, results from this proposal will elucidate midlife risk transducers of AD pathology and dementia. In this investigation, we will prospectively collect blood plasma, MRI, and PET biomarkers of AD and neurocognitive data in a sample of 300 WSC participants who are now older aged, to address two Specific Aims with testable hypotheses supported by preliminary data: Aim 1 will identify the effects of more severe OSA and poorer midlife CRF on multiple AD biomarkers, determine whether midlife OSA and CRF delay the age of amyloid onset, a key indicator of AD pathology, and examine if trajectories of OSA and CRF interact to predict AD pathology in later life; Aim 2 will determine whether similar patterns of OSA and fitness are associated with clinical endpoints of cognitive decline and dementia. For all Aims, it is expected that higher CRF will serve as a protective factor, moderating relations between OSA and AD pathology and cognitive decline. Detailed sleep and health history data available in the WSC allows for key covariates to be evaluated in analyses interrogating our Aims. Addressing the Aims of this application will fill a significant and critical need in AD research by capitalizing on an existing cohort with extensive midlife phenotyping of two salient lifestyle factors associated with lower AD risk. In so doing, this project will ultimately lead to improved preventative and therapeutic strategies t...