PROJECT SUMMARY/ABSTRACT This proposal seeks to expand the understanding of Alzheimer?s disease (AD) pathophysiology with the ultimate goals of enhancing care by ensuring timely/accurate diagnosis, as well as preventing and effectively treating AD. AD afflicts over 5 million people in the US and no current therapy modifies the course of AD. Positron Emission Tomography (PET) imaging has been successfully employed to investigate changes in living humans at the molecular level, aiding in the diagnosis and understanding of AD. Therefore, the neurobiology of AD can be studied in vivo with multi-tracer neuroimaging and neuropsychological characterization. Molecular changes at the synaptic level are associated with AD. Metabotropic glutamate receptor subtype 5 (mGluR5) is present at synapses throughout the cortex and is a mediator of amyloid ? induced AD pathology. Therefore, mGluR5 is a candidate biomarker for AD and a target for therapeutic intervention, making its detection in AD an important goal. Furthermore, synaptic vesicle glycoprotein 2A (SV2A) is a pre- synaptic protein with potential as the first in vivo marker of synaptic density. Since synaptic loss is observed in the earliest stages of AD, SV2A binding stands to be a robust marker of disease progression. The long-term objective of this proposal is to apply PET methods to understand the neurobiological changes associated with AD using [18F]FPEB, a specific ligand for mGluR5, and [11C]UCB-J, a specific ligand for SV2A (synaptic density). This is likely to have a significant impact by (i) determining the changes in mGluR5 receptor availability that occur during AD (Aim 1), (ii) determining the changes in synaptic density that are detectible during AD (Aim 2), and (iii) understanding the relationship between changes in mGluR5 receptor availability and synaptic density (Aim 3). These investigations will provide valuable understanding of the AD disease process and lead to the development of both novel treatments and therapeutic biomarkers. The proposed program will integrate state-of-the-art biomedical imaging facilities at the Yale School of Medicine with the robust resources of the Yale Alzheimer?s Disease Research Center. The mentorship team consists of internationally renowned experts in AD diagnostics and therapeutics, human PET imaging, and biostatistics. The program will provide the candidate with the skills and experience to become an independent investigator in the fields of AD neurobiology and PET imaging. Specific training goals include: (i) developing advanced skills in the conduct of human AD and PET research, (ii) developing expertise in computational and statistical methods for PET tracer kinetic modeling and image analysis, and (iii) developing an independent program of AD molecular neuroimaging, all in order to ultimately sustain an independently funded research career. The career development award proposes structured opportunities designed to develop an expertise in innovative neurobiological research methods and a career as an independent AD and cognitive disorders investigator.