Abstract. Alzheimer’s disease (AD) is presently an untreatable neurodegenerative disorder with a massive public health burden. With invention of biomarker technologies for imaging β-amyloid (Aβ) plaques and neurofibrillary tangles in the living human brain, it became clear that these pathologies that define AD begin decades prior to overt dementia symptoms resulting from this disease. This prolonged pre-dementia period offers opportunities for early interventions. However, much is currently unknown about the complex AD pathophysiology in these early stages. One intriguing observation is that the early Aβ pathology is often localized to highly metabolic regions of the brain. These regions, also known as ‘cortical hubs’ due to their high functional interconnectivity with other brain areas, may display activity related susceptibility. Animal models show that, in functionally active brain regions, disrupted rapid temporal structure of intrinsic neural activity and neurovascular dysregulation can influence Aβ homeostasis. It is possible that these pathophysiological mechanisms hold true in the aging human brain. However, precise measurement of rapid neural activity and neurovascular regulation in the higher-order brain areas most vulnerable to AD has been challenging. Currently available imaging techniques, when used alone, have severe limitations. The signal measured by functional magnetic resonance imaging (fMRI) reflects coupling between metabolic demand of active brain cells and a nutritive increase in cerebral blood flow and cannot differentiate between dysfunctions in neural activity itself and this neurovascular coupling (NVC). Techniques, such as electroencephalography (EEG), cannot unambiguously localize the recorded neurophysiological signal to specific neural networks. To overcome this critical barrier, we developed a cutting-edge scanning and analysis paradigm that [1] simultaneously records EEG and fMRI data, [2] detects and quantifies short timescale structure of transient events of intrinsic neurophysiological activity in cortical networks, and [3] uses these neural network events to anchor assessment of capacity to adjust vascular energy delivery in response to activity demands. Such selective measurements in unique neural networks will be used in the current project to test if disrupted rapid neural function and NVC in the active ‘cortical hubs’ are associated and show temporal precedence to Aβ pathology and the linked deficits in higher-order cognitive domains in a longitudinal cohort of older adults without clinical dementia. We will quantify Aβ pathology by leveraging novel ultra-sensitive blood biomarkers. Successful implementation of this approach would suggest that, in the aging human brain, abnormal fast neural dynamics and NVC in specific cortical regions are disease states predisposing to Aβ pathological changes. If such disease states are an upstream process to Aβ pathology, then in future studies, it may be possible to regu...