Project Summary/Abstract Recent studies in rodents demonstrate the existence of a brain-wide glymphatic system, which transports bulk flow of cerebrospinal fluid (CSF) from the subarachnoid space into the brain parenchyma through the para- arterial and para-venous spaces. This CSF flow flushes out interstitial soluble Aβ, tau and other toxic proteins, ultimately influencing brain Aβ and tau protein homeostasis. The presence of intracranial pulsatility is recognized as the driving force for the convection of CSF through these pathways. However, whether this mechanism functions similarly in humans remains unknown. Hypertension accelerates brain aging and increases the risk of Alzheimer's disease (AD). The underlying mechanism(s) are not well understood. Our recent studies and others have demonstrated that elevated central pulsatility is associated with brain atrophy and white matter lesions. How changes in central pulsatility are transmitted downstream into cerebral microcirculation to generate intracranial pulsatility, and whether changes in intracranial pulsatility affect brain Aβ and tau homeostasis also remain unknown. The overarching goal of this project is to test the hypothesis that intensive antihypertensive treatment alters central and intracranial pulsatility which in turn affect brain Aβ and tau protein homeostasis. Furthermore, we will determine whether changes in intracranial pulsatility, Aβ and tau are associated with brain white matter integrity and neural network functional connectivity. To achieve this goal, we will enroll 120 older adults age 60-79. Of those, 40 have normal blood pressure (BP) (24-h BP<130/80 mmHg) and 80 have high systolic BP (24-h SBP ≥140). Patients with hypertension will be randomized into a 12-month intensive treatment arm (24-h SBP≤125) and a control arm of the standard care (24-h SBP≤140). Aim 1: Determine the effects of hypertension on intracranial pulsatility, CSF Aβ and tau, brain white matter integrity, and neural network functional connectivity. Hypotheses: Hypertension is associated with: 1) augmented central pulsatility, but reduced intracranial pulsatility; 2) reductions in CSF soluble Aβ42, but increases in phosphorylated tau and total tau; 3) disruptions in brain white matter integrity inferred by diffusion tensor imaging, and functional connectivity by resting-state fMRI. We also will determine whether group differences in intracranial pulsatility, brain Aβ, and tau are associated with white matter integrity and neural network functional connectivity; Aim 2: Determine the effects of antihypertensive treatments on intracranial pulsatility, CSF Aβ and tau, brain white matter integrity and neural network functional connectivity. Hypotheses: compared to standard care, intensive treatment confers more benefits by: 1) reductions in central pulsatility, but increases in intracranial pulsatility; 2) increases in CSF Aβ42, but reductions in phosphorylated tau and total tau; 3) improvement in brain white m...