PROJECT SUMMARY/ABSTRACT The proposed work is designed to prepare the applicant with training necessary to establish an independent investigator in the field of interdisciplinary biomedical imaging science, with particular focus on MRI-based assessment of neurodegenerative disease. The central core of the training will involve closing the gap between the applicant's biophysics background and her limited exposure to pathophysiology and clinical research in order to enhance understanding of the clinical implications and biomedical needs of novel MRI techniques toward translating imaging methodology to the clinical applications. Early diagnosis of Alzheimer's disease (AD) is critical for developing therapeutic strategies to prevent, slow or even halt progressive disease. A growing body of evidence suggests cerebrovascular dysfunction may occur relatively early and proceeds the cognitive decline and onset of neurodegenerative changes in AD. Vascular compliance (VC) or arterial stiffness is an important indicator of vascular dysfunction. Currently, VC can be only assessed from central and peripheral arteries using pulse wave velocity (PWV). Recently, we have developed a non-invasive MRI technique for assessment of intracranial VC using dynamic arterial spin labeling (ASL). The goal of the research component of this proposal is to further develop and optimize the noninvasive intracranial VC techniques, and to evaluate intracranial VC as an early imaging marker by comparison with other established biomarkers. We hypothesize that intracranial VC is able to serve as an early imaging marker in the development of AD. The hypotheses will be addressed with the following three specific aims: 1) We will further develop and optimize the intracranial VC technique to improve the reliability of VC measurement. 2) We design a cross-sectional study to measure and compare intracranial VC in four age-equivalent groups including cognitively normal (CN) and mild cognitive impairment (MCI), with and without APOE ϵ4 genotype. 3) We correlate intracranial VC with the established AD biomarkers. The expected outcome is a noninvasive MRI tool for assessment of intracranial VC or arterial stiffness, and developing intracranial VC as an early imaging marker of AD, which may deepen our understanding of cerebrovascular contributions to AD pathogenesis. This career development award will provide the applicant necessary training to integrate her expertise with clinical translational studies and develop into an independent investigator.