Neurovascular dysfunction has been linked to AD evolution in experimental, imaging, pathological, and epidemiological studies. These key findings have led to an emerging ‘neurovascular hypothesis’ of AD, which holds that cerebrovascular dysfunction contributes to the onset and progression of cognitive decline. Project 3 will test this hypothesis using a novel rat model of AD (line TgF344-AD) harboring two transgenes that are independently causative of early autosomal AD: ΔE9 presenilin 1 (PSEN1) mutation and human ‘Swedish’ amyloid precursor protein. TgF334-AD rats faithfully recapitulate the rich clinico-pathological spectrum of human AD including cognitive/behavioral deficits, amyloid-β (Aβ) deposition, tau pathology, and neuronal loss, and develop an early neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown and injury to BBB-associated cells, pericytes, prior to Aβ deposition, tau pathology, neuroinflammation and neuronal loss, as we show preliminarily. Based on our preliminary findings we hypothesize that vascular/BBB dysfunction is an early pathogenic event that precedes and predicts onset and progression of behavioral and neurodegenerative changes in TgF3444-AD rats, and that manipulation of BBB integrity impacts the disease course. To test our hypothesis we will use cutting-edge approaches: 1) a novel molecular biomarker assessment of the neurovascular unit (NVU) in biofluids (cerebrospinal fluid, CSF; plasma) to determine how vascular/BBB injury relates to neuronal injury and responses of non-neuronal neighboring cells (e.g., astrocytes, microglia, inflammatory response), Aβ and tau; 2) advanced neuroimaging assessment of neurovascular function using a dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) of BBB permeability, dynamic susceptibility contrast imaging (DSC-MRI) of cerebral blood flow (CBF) and diffusion tensor imaging (DTI-MRI) tractography; 3) behavioral assessment; and 4) brain tissue analysis. We will evaluate NVU biomarkers in CSF, plasma and tissue by age and in relation to cognitive function, behavior and AD-like neuropathology in Tg344-AD rats compared to control rats (AIM 1); examine longitudinally regional BBB permeability (DCE-MRI) and CBF (DSC-MRI) (AIM 2), and structural connectivity (DTI-MRI) (AIM 3) in relation to cognitive and behavioral function and AD-like neuropathology in Tg344-AD rats compared to control rats; and, determine whether therapeutic manipulation of the BBB to prevent early BBB breakdown (AIM 4) or mechanical manipulation to advance the degree of a spontaneous early BBB breakdown (AIM 5) in TgF344- AD rats can impact the disease course and neuropathology. Understanding how neurovascular integrity relates to brain connectivity and AD neuropathology will be a critical advance towards discovering how these factors influence cognitive impairment. Project 3 is essential for this P01 because it provides the only way to experimentally manipulate the vascular system t...