Project Summary The major theory of causation for Alzheimer’s disease (AD) is deposition of the protein β-amyloid, however it is unclear how aging influences amyloid accumulation or why cognitive decline can occur in its absence. Evidence suggests that neurovascular dysfunction, such as the breakdown of the blood-brain barrier (BBB), is related to neurodegeneration and cognitive impairment, and that this relationship may occur independently of amyloid. However, the direct relationship between BBB breakdown and AD biomarkers, as well as cognition, has not been thoroughly investigated in humans. The aim of this study is to use a novel multi-modal imaging design to examine how BBB breakdown in humans is related to AD biomarkers of atrophy, amyloid and tau, and cognition. BBB breakdown will be quantified in vivo using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows for the detection of subtle BBB leakage in the human brain. Both tau and Aβ will be measured in vivo using the positron emission tomography (PET) tracers [18F] Flortaucipir and [11C] PiB, respectively. Neurodegeneration will be measured with structural MRI and episodic memory with a composite neuropsychological test score. Aim 1 will determine if BBB breakdown increases with age and if there are specific regions that are more vulnerable during normal aging. Aim 2 will examine if BBB breakdown in the temporal lobe is related to greater global Aβ and regional tau. In addition, it will be determined if BBB breakdown is associated with greater retrospective longitudinal Aβ and tau accumulation. Finally, Aim 3 will determine if BBB breakdown in the temporal lobe is related to smaller temporal lobe volumes and worse memory performance. Relationships between BBB breakdown and retrospective longitudinal change in memory performance, independent of amyloid and tau, will also be examined. The findings from this study will help unravel fundamental mechanisms of AD pathogenesis in the human brain, which has vital implications for early detection and the development of new treatment strategies for AD. The proposed research project will achieve the applicant’s training goals, which include (1) developing skills in multimodal imaging, (2) advanced statistics and data analysis training, (3) training in clinical impairment and pathophysiology of AD, (4) development of teaching and mentoring skills, (5) improvement of effective scientific communication skills, and (6) career development. UC Berkeley’s Helen Wills Neuroscience Institute is home to a network of cutting-edge researchers and world-class imaging facilities. The sponsor of the project, Dr. William Jagust, is at the forefront in applying multimodal neuroimaging methods to study questions of aging and AD. He also has successfully mentored numerous students in the past, who have become leaders in the field. The co-sponsor, Dr. Suzanne Baker, is an expert in optimization of neuroimaging quantification for both PET and MRI...