Project Summary Alzheimer’s disease (AD) is a progressive disorder that is currently the leading cause of dementia worldwide. AD pathology is marked by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain, leading to neuronal dysfunction and cell death. The recently characterized glymphatic system, thought to be important for the clearance of β-amyloid, has increasing relevance in the context of AD pathogenesis. Furthermore, the astrocytic water channel aquaporin-4 (AQP4) serves a critical role in the glymphatic system by facilitating the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). Rodent models and post-mortem histological analysis of human brains point to upregulation and mislocalization of the AQP4 channel in AD. This mislocalization is theorized to hinder the convective flow of fluid through the interstitium and exacerbate amyloid accumulation. Importantly, the dystrophin-associated complex (DAC) serves as the primary molecular regulator of AQP4 localization, and genetic deletion of specific DAC components leads to mislocalization of the AQP4 channel. Despite this evidence, changes in AQP4 and DAC gene expression and its influence on AD pathology have yet to be explored in large-scale human studies. To further investigate how changes in AQP4 and DAC genotype and expression affect AD-relevant outcomes, our group intends to leverage computational approaches in large and well-characterized studies of aging and AD. Using bulk RNA sequence data from the Religious Orders Study (ROS) and Memory and Aging Project (MAP), we will be able to identify associations of AQP4 and DAC gene expression with amyloid and tau burden measured at autopsy. Further, we will pair our transcriptomic data with harmonized metrics of cognition, thus allowing for the examination of downstream consequences of AD pathology. Finally, we will incorporate an innovative approach using PrediXcan to separate causation from correlation by leveraging advanced models that determine levels of genetically-regulated gene expression. A benefit of this approach is the ability to greatly expand statistical power by incorporating additional cohort studies of aging and determine the effect of AQP4 and DAC genetic regulation on neuropathology and cognition. To fulfill the research aims of this F31 application, we will leverage exceptional resources at Vanderbilt University and the Vanderbilt Memory & Alzheimer’s Center. The candidate, Jared Phillips, will conduct the proposed research with the support of an interdisciplinary mentorship team, including experts in the neurobiology and genetics of AD, geriatric neuropsychology, neuroscience, and glymphatics. The parallel training plan will provide Jared Phillips with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful independent scientist working to improve the field’s understanding of glymphatic contributions to AD. Res...