PROJECT SUMMARY Alzheimer’s disease, the most common cause of dementia and the sixth most common cause of death, afflicts nearly 6 million people in the United States. Alzheimer’s disease is a major economic burden to our society with an annual cost of more than $250 billion. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries is critical as these arteries dampen the pulsatile pressure and protect the microcirculation and blood brain barrier from damage. Cerebrovascular dysfunction can have detrimental impacts on the brain. Growing evidences suggest that cerebrovascular dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease and can potentially be used as a biomarker for preclinical Alzheimer’s disease. The overall goal of this project is to unravel the close relationship between cerebrovascular remodeling and the progression of Alzheimer’s disease. Our preliminary study suggested that with pathological progression of Alzheimer’s disease, the human cerebral artery showed progressive stiffening, structural breakdown, and increases smooth muscle cell atrophy. We thus hypothesize that the structural and functional changes in large cerebrovasculature is correlated with neurodegeneration and the accumulation of Amyloid-β, other toxic metabolites, and tau pathology in the brain. Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology and neuropathology of Alzheimer’s disease, we will test this hypothesis in three aims: Aim 1) to determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal and temporal lobes in Alzheimer’s disease; Aim 2) to determine the association between cerebrovascular remodeling and Alzheimer’s disease pathological changes in the frontal and temporal lobes of the brain; and Aim 3) to examine the association between cerebrovascular remodeling and antemortem cognitive status and neuropsychological test performance. We will use no or low atherosclerotic cerebrovascular and brain tissue from 100 age- and sex-matched brain donors from the NIA-funded BU Alzheimer’s Disease Research Center with 1) no Alzheimer’s disease pathology, 2) low Alzheimer’s disease pathology, and 3) intermediate/high Alzheimer’s disease pathology . These brain donors have completed annual National Alzheimer’s Coordinating Center Uniform Data Set evaluations during life and have available consensus-based cognitive diagnoses. This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling and AD. Understanding the role of vascular remodeling in Alzheimer’s disease may lead to the discovery of new treatment options and directions for interventions to stave off Alzheimer’s disease.

PROJECT NARRATIVE Cerebral arteries are critical for proper function of the brain. The proposed research aims to study the associations between changes in cerebral arteries and the progression of Alzheimer’s disease as well as cognitive impairment. Such understandings may lead to the discovery of new treatment options for Alzheimer's disease.