PROJECT SUMMARY/ABSTRACT Perivascular space (PVS) pia is a unique tissue composite within the mammalian nervous system and is traversed by cerebrospinal fluid (CSF) during CSF-interstitial fluid exchange. PVS are known to become more complex with aging. Accumulating evidence suggests that PVS subserve specialized roles in glymphatic- lymphatic transport and may be a critical factor in brain resilience and diseases, including Alzheimer’s disease. In spite of this, the basic structure of brain pia is minimally investigated across species. Historically, pia has been perceived to play passive roles as an ultrafine membrane that restricts fluid movement at the brain surface. Substantial gaps in knowledge remain regarding the specific morphology and constituents of this meningeal layer and its associations with disease, due in large part to lack of systematic and high-resolution microscopic analyses. To advance the field, better characterization of pia structure is needed. In this project, high-resolution microscopy techniques will be used to elucidate the morphology of human pia mater and its morphological and compositional changes with aging. Pial anatomy will be mapped using immunohistochemical techniques and its properties will be correlated with established neuropathological and neurological measures of disease. For this work, we will leverage a rich resource of clinical and pathologic material available from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) and will collect and analyze novel data pertaining to the unique structure of PVS pia. The hypothesis is that PVS pia functions as a critical neuroimmune tissue and that pial senescence is associated with Alzheimer’s disease (AD). In Aim 1, we will examine the associations of pial morphology with intracranial beta-amyloid (βA) accumulation and pathology of AD. In Aim 2, we will examine the associations of pial morphology with cognitive decline and resilience. In Aim 3, we will explore the associations of pial morphology with PVS and brain inflammation. In each aim, we will investigate how relationships differ by age, sex, and comorbid diseases. Overall, these studies have the potential to uncover new knowledge regarding the function of pia mater in aging and AD as well as novel insights into its heterogeneity in aging. The proposed investigations will advance the field and may reveal mechanistic, diagnostic and prognostic factors for AD while laying a framework for studying this meningeal layer in the setting of other age-related neurological diseases.