ABSTRACT Synaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). New positron emission tomography (PET) radioligands have been developed which bind to synaptic vesicle glycoprotein 2A (SV2A), a synaptic vesicle protein found in presynaptic nerve terminals throughout the brain. While development of these tracers is a major advance for the field of AD, very little is yet known about synapse loss across the clinical and pathological spectrum of AD, and longitudinal studies in large cohorts are lacking. In order to address this gap in knowledge, we propose to perform longitudinal SV2A PET imaging with [C-11]UCB-J in participants recruited from the Wisconsin Alzheimer’s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative participants, cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will be imaged at baseline and at two- year follow-up. The hypothesis is that regional synaptic loss will serve as a sensitive marker of neurodegeneration in the context of plaque and tangle accumulation and will explain cognitive decline. In order to address this hypothesis, we propose the following three specific aims: 1) determine the extent to which [C- 11]UCB-J provides unique information from MRI regarding neurodegeneration; 2) determine the rate of synapse loss as reflected by [C-11]UCB-J signal; and 3) determine the extent to which [C-11]UCB-J associates with cognitive decline. In addition to [C-11]UCB-J PET, we will acquire [C-11]PIB PET to determine spatial amyloid plaque burden, as well as [F-18]MK6240 PET to determine tau tangle burden. This study will be the first to obtain these three markers in tandem, which will allow—for the first time—the ability to determine how these pathologies evolve in AD, and determine how they are spatially and temporally related to one another. The National Institute on Aging has called SV2A PET imaging a “potentially game-changing biomarker in AD and AD-related dementias”. Synapse loss is expected to be the most closely associated with cognitive decline, yet no large human studies have yet been undertaken to examine regional synapse loss across the spectrum of AD. The proposed project addresses this gap in knowledge. This program of research is expected to improve early detection of AD, improve prediction of cognitive decline, and inform the development of new treatment strategies.