Project 2 Summary/Abstract Health risk factors such as cardiovascular risk factors (CVRF) and poor sleep are thought to increase the risk of Alzheimer’s disease (AD). While the mechanisms linking CVRF and poor sleep with AD pathology remain unclear, neuroinflammation such as astrogliosis, may be one such pathway. CVRF has consistent links to AD pathology: during the past 10 years of this program project, we explored the relationship of Aβ deposition alone and in combination with vascular modulators to neuronal dysfunction, and their association with progression to cognitive impairment and AD. We identified associations of increased arterial stiffness, systolic blood pressure, and cholesterol homeostasis with increases in Aβ burden In addition to CVRF, sleep is implicated as a risk factor for AD. Sleep has well-established links to brain structures and pathways implicated in AD, and is essential to cognitive, immune, and other physiological functions. Age- and disease-related sleep changes may influence the accumulation of AD pathology21, 22. Sleep loss is associated with increased levels of Aβ in the interstitial space, and influences kinetics of Aβ and tau in the cerebrospinal fluid. We and others have demonstrated that poor sleep quality and lower objective sleep efficiency (see preliminary data) are associated with greater Aβ burden. Moreover, through this program project, we found a stronger association between Aβ and forgetting in those with poorer sleep efficiency. Together, these data suggest that CVRF and poor sleep may create a state of vulnerability to AD pathology. Nonetheless, the mechanisms by which these health factors can create this increased vulnerability to AD remain unclear. One potential mediating factor is neuroinflammation. Cellular inflammation plays a well- established role in AD pathology. Inflammation has established links with CVRF, hypertension, and stroke risk. Similarly, sleep loss induces a 3-fold increase in pro-inflammatory cytokines, which contribute to the homeostatic drive for SWA. Moreover, chronic poor sleep leads to a cascade of chronic neuroinflammation including astrogliosis and microglial activation. Together, these data suggest that CVRF and poor sleep may accelerate the process of Aβ deposition partially through neuroinflammation. The overarching goal Project 2 is to understand the role of astrogliosis, as a marker of neuroinflammation, in the relationship between health risk factors (CVRF and sleep) and the trajectory of AD pathophysiology. In 300 participants we will complete longitudinal assessments of: 1) Clinical vascular measures of CVRF and sleep efficiency and SWA assessed with actigraphy and polysomnography; 2) Astrogliosis using PET (SMBT-1) and plasma (GFAP); and 3) AD pathology including Aβ-PET, plasma Aβ, tau PET, and plasma tau. We will examine cross-sectional and longitudinal associations of CVRF and sleep with pathology and the mediating role of astrogliosis. We will explore whether chan...