PROJECT SUMMARY Research on Alzheimer’s disease has strongly focused on pathological alterations such as plaques and tangles, and has overlooked the functional consequences of neuronal firing. Compelling evidence from animal models and basic science investigations have shown that functional consequences of Alzheimer’s disease proteinopathy starts even before the beta-amyloid (Aβ) and tau form into detectable pathological aggregates. Abnormal neuronal firing patterns in individuals during the predementia stage of Alzheimer’s disease therefore may signify the presence of incipient neurodegenerative processes. Neural oscillations detected from electrophysiological techniques with high spatiotemporal resolution such as magnetoencephalography (MEG) have the potential to detect and quantify subtle changes in abnormal neuronal firing patterns in the human brain. To pursue novel directions and fill important knowledge gaps in the field, the proposed project is aimed to elucidate the role of neuronal dysfunction and hyperexcitability in the early biological progression of Alzheimer’s disease. Defining the electrophysiological signatures in the predementia stage of Alzheimer’s disease will identify the earliest neural circuit abnormalities, broaden the current conceptualizations of disease pathogenesis, and provide novel insights for early interventional clinical trials. We will conduct a longitudinal, multimodal imaging study, including clinical cohorts of Aβ+predementia individuals (Aβ+ cognitively unimpaired, Aβ+CU and Aβ+ mild cognitive impairment, Aβ+MCI) and Aβ− CU controls. Participants will be assessed at bassline and at 2- year follow-up. Aβ-positron emission tomography (PET) at baseline will determine the Aβ+/− status in each participant, and multimodal neuroimaging (MEG, tau-PET, MRI), and clinical evaluations will be performed at baseline and at 2-years. Our central hypothesis is that, in the presence of Aβ, regional neural circuit hyperexcitability contributes to progression of Alzheimer’s disease tauopathy and cognitive decline. We will address two specific aims: AIM-1 will identify the earliest manifestations of neural circuit hyperexcitability that will predict accumulation of regional tau in Aβ+predementia, and also will define the role of specific excitatory and inhibitory neuronal subpopulation abnormalities as mediators of tau accumulation. AIM-2 will determine the earliest manifestations of neural circuit hyperexcitability that will predict cognitive deficits that can be detected in Aβ+predementia. This project will determine the critical role of neuronal hyperexcitability in early Alzheimer’s disease pathogenesis in the human brain and develop a framework to assess neural circuit hyperexcitability in the earliest disease stages. The findings will help link cellular findings from basic science to clinical disease in patients with Alzheimer’s disease. By establishing the role of network hyperexcitability in Alzheimer’s disease progressi...