Project Summary/Abstract: Extant literature suggests that damage to the blood-brain barrier (BBB) is intricately involved in the pathogenesis of Alzheimer's disease and related dementia (ADRD). For example, post-mortem studies demonstrated that ADRD brain is characterized by the accumulation of blood-derived proteins, degeneration of BBB-specific cells, and injury of vascular endothelium. However, the relationship of BBB damage to pathological hallmarks of dementia such as beta-amyloid, tau, and cerebral small vessel disease are not well understood, particularly in humans. This is primarily attributed to a scarcity of in vivo techniques to evaluate BBB function. The PI is a leading expert in non-invasive imaging of microvascular function, and his laboratory has recently developed, optimized, and validated a MRI technique to assess BBB permeability to water molecules. Our preliminary studies using this novel technique has shown strong evidence that 1) Significant BBB breakdown can be detected in patients with mild cognitive impairment (MCI) using non-contrast MRI; 2) the extent of BBB breakdown is associated with amyloid burden; and 3) BBB function can predict cognitive function, particularly in the memory domain. The central goal of this application is therefore to capitalize on these technical advances and characterize BBB breakdown in MCI and early dementia, and to understand its causal relationship to both AD and small vessel pathology. BBB permeability to three molecules of different sizes, specifically water (molecular weight 18 g/mol), Gadolinium MRI contrast agent (molecular weight 547 g/mol), and albumin (molecular weight 66K g/mol) will be measured in the same participants. Human patient studies will be paralleled by studies in animal models so that clinically relevant discoveries can be validated in experimental models. The role of inflammation in BBB breakdown will also be examined. These relationships will be studied in both cross-sectional and longitudinal manner. This multi-modality, multi-disciplinary project has three Aims. Aim 1 will examine the cross-sectional relationship between BBB breakdown, amyloid, tau pathology, small vessel pathology, and inflammatory markers in 125 elderly participants including cognitively normals, MCI, and early dementia. The inter-relationships among these variables will be studied in the framework of a mechanistic model. Aim 2 will conduct a 30-month follow-up of these participants and investigate the longitudinal relationship between BBB breakdown and progression of AD pathology, small vessel pathology, inflammatory markers, and cognitive function. Finally, in Aim 3, we will validate the pathological underpinnings of BBB dysfunction in ADRD using two novel rodent models that our collaborators have developed for AD and small vessel disease, respectively. These rodent models with relatively pure pathology are expected to reveal more definitive relationships between BBB breakdown and AD and small ve...