INTRODUCTION: POINTER Neurovascular (POINTER-NV) is an ancillary study that leverages the rich infrastructure and design of the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to investigate neurovascular mechanisms that may underlie intervention effects on key brain outcomes. METHODS: A comprehensive neurovascular assessment is conducted at baseline, Month 12, and Month 24 using a variety of complementary non-invasive techniques including transcranial Doppler ultrasound, carotid ultrasound, echocardiography, tonometry, and continuous blood pressure and heart rate monitoring. Measurements are acquired at rest and during orthostatic challenges, hyperventilation, and carbon dioxide inhalation. RESULTS: The primary outcomes are baroreflex sensitivity and cerebral autoregulation. Secondary outcomes include aortic, carotid, and cerebral hemodynamics and various measures of autonomic function and vascular structure and function. DISCUSSION: POINTER-NV will provide critical insight into neurovascular mechanisms that may change with intensive lifestyle modification and promote improvements in cognition and overall brain health. HIGHLIGHTS: This study takes advantage of U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) to address key gaps in the field. POINTER Neurovascular (POINTER-NV) will provide insight into neurovascular mechanisms underlying dementia. POINTER-NV may help shed light on modifiable vascular contributions to dementia.