Identification of early brain dysfunction in Alzheimer's disease (AD) that contributes to the ultimate accumulation of amyloid is critically needed so that we can therapeutically halt disease progression before major, irreversible brain damage occurs. To date, our understanding of AD has been dominated by post mortem human brain data and without tools to 'see' into the living brain, it is impossible to visualize the molecular changes that precede disease onset. Molecular imaging with techniques like positron emission tomography (PET) has proven valuable at measuring disease after onset (for example, using amyloid PET radiotracers); unfortunately, imaging biomarkers of "downstream" protein aggregates like amyloid reveal disease status too late. Thus, there is an urgent need and opportunity to measure "upstream" biological processes that are critical control points for gene expression and disease onset. One of these "upstream" processes is known as chromatin remodeling, which is controlled in part by an enzyme family called the histone deacetylases (HDACs). A key subset of this family, the class I isoforms, has been shown to be dysregulated in the brains of patients with AD and in animal models has shown remarkable therapeutic potential for improving cognitive function that results from early neurodegeneration.Our lab has developed the first, and to date only, imaging agent for class-I HDAC and has successfully progressed the imaging agent to first-in-human trials. We are uniquely positioned to now determine whether our HDAC imaging agent named [11C]Martinostat could serve as an early imaging biomarker of AD. Our experiments will answer the question, is HDAC expression altered in the aging and AD brain? Importantly, either positive OR negative outcomes will provide an immediate step forward in understanding AD and motivate novel drug trials; evaluating HDAC expression in vivo provides a unique opportunity to intervene in patient health.