PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) has been called a synaptic failure. Indeed, synaptic loss is a prominent AD pathology and the major structural correlate of cognitive impairment in AD. AD is characterized by a distinct pathology, with plaques composed of amyloid-β (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, and a loss of synapses. Synaptic damage is observed in the earliest stages of AD, with Mild Cognitive Impairment (MCI) patients demonstrating a loss of synapses and several presynaptic proteins. Thus, the ability to assess synaptic density in vivo is of high utility in studies of AD as well as in monitoring potential therapies. Positron Emission Tomography (PET) imaging is increasingly employed in AD studies to measure glucose metabolism (18F-fluorodeoxyglucose, 18F-FDG), Aβ, and NFTs. However, tracers for new molecular targets are needed to directly monitor loss of synaptic density. One suitable target is the synaptic vesicle glycoprotein 2 (SV2), an essential vesicle membrane protein. One of its isoforms, SV2A, is ubiquitously expressed in virtually all synapses and is involved in regulation of synaptic trafficking. We recently developed 11C-UCB-J, a PET tracer for quantitative SV2A imaging in vivo and carried out the first-in-human studies, which have shown high brain uptake and excellent reproducibility. Our preliminary experience with 11C-UCB-J in early AD has demonstrated significant reductions (44%) in hippocampal SV2A binding, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to the hippocampus (via the perforant path) and hippocampal SV2A reductions observed in postmortem studies. However, we critically need to relate synaptic density with 11C-UCB-J to other markers of AD pathogenesis (in particular, tau deposition) and to expand the study of synaptic loss to the earliest—preclinical—stages of disease, using an established cohort. Thus, we propose the following Specific Aims: Aim 1: To investigate in individuals with symptomatic AD the association of SV2A binding (using 11C-UCB-J) with tau deposition (using 18F-MK6240). Aim 2: To investigate the association of familial and genetic AD risk in cognitively normal (CN) middle-aged individuals with: a) hippocampal SV2A binding and b) ERC-tau deposition. Aim 3: To investigate the associations between SV2A binding and Aβ, as well as tau deposition in cognitively normal middle-aged individuals at varying AD risk. In vivo assessment of synaptic density will enable the study of the early emergence of synaptic loss and the integration of this information with other biomarkers of disease, including Aβ and tau deposition, providing a more comprehensive model of disease.