Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, a relentless and fatal condition of progressive cognitive deficits. The urgency to find a cure for AD has never been stronger. Synaptic dysfunction and synapse loss are core deficits in AD pathophysiology. A better understanding of synaptic dysfunction in AD is imperative to develop effective therapeutic interventions. In this R21, we propose a multimodal imaging study combining structural and functional synaptic measures simultaneously to characterize synaptic failure in patients with AD. The multimodal composition of our study includes magnetoencephalography (MEG) to probe synapse physiology and positron emission tomography (PET) to probe synapse density, together with in-vivo quantification of amyloid (Aβ) and tau depositions. This proposal represents one of the very first to combine two sophisticated technologies to study synaptic failure in AD. On one hand, MEG provides quantitative spectral signatures of neural oscillations which represents the most direct, non-invasive, measures of neuronal and synaptic function in the human brain. Combining the fine spatiotemporal resolution of MEG spectral analyses with mathematical application of neural mass model (NMM) is a powerful technique to examine neuronal level details from non-invasive neuroimaging in human subjects. On the other hand, radioligands that bind to the synaptic vesicle glycoprotein 2A (SV2A) has recently become available to measure in-vivo synaptic density in the human brain. Here we propose to use a new second generation SV2A ligand, 18F-SynVesT-1, for the first time in AD research. Defining the relationships between synaptic density and synapse physiology and their specific relationships to Aβ and tau will broaden the current conceptualizations of AD pathophysiology and provide novel synaptic biomarkers for early interventional clinical trials. We will conduct a cross sectional pilot study of 45 participants: 25 Aβ-positive mild cognitive impairment (MCI) and mild-AD-dementia (CDR<1), and 20 age-matched cognitively unimpaired individuals (10 Aβ-negative and 10 Aβ-positive). All participants will undergo resting state MEG, structural MRI, 3-tracer PET imaging for SV2A (18F-18F-SynVesT-1), Aβ (florbetaben), and tau (flortaucipir), and complete cognitive and neuropsychological assessments. Our central hypothesis is that excitatory and inhibitory neuronal deficits will be correlated with reduced synaptic density (18F- SynVesT-1), and with Aβ and tau depositions (florbetaben and flortaucipir, respectively) in early clinical stage of AD. We will address two key aims. In Aim 1, we will determine the relationship between impaired synapse physiology (MEG and NMM) and synapse density (18F-SynVesT-1 retention) in AD. In Aim 2, we will Examine the associations between binding deficits of 18F-SynVesT-1 PET and AD pathophysiology and cognitive impairments in early clinical stage AD patients. This project will g...