Evaluation of Monoamine Oxidase-A as a New Biomarker for Alzheimer's Disease Project Summary This application is in response to PAR-19-071, “Research on current topics in Alzheimer's disease and its related dementias (ADRD)”. Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaque aggregation and Tau protein paired helical filaments causing neurofibrillary tangles (NFT) in the brain. Noninvasive brain imaging methods and peripheral measures of phosphorylated Tau isoforms (pTau181 and pTau217) are becoming reliable markers for AD. In addition to these biomarkers, translocator protein (TSPO) as a marker for inflammation is also being pursued in efforts to gain a comprehensive understanding of disease etiology. Imaging methods play a key role in understanding NFT accumulation in AD beginning in the entorhinal cortex and hippocampus, spreading to the temporal cortex and subsequently to the neocortex. Monoamine oxidase A (MAO-A), a mitochondrial enzyme found in neurons, deaminates monoamine neurotransmitters. Upregulation of MAO-A can cause oxidative stress leading to neurodegeneration. Currently, no PET imaging studies have been reported on MAO-A in AD patients. [11C]Harmine, a MAO-A PET radiotracer has been used in human studies of depression, but no reports exist in AD. In autoradiographic studies using [18F]FEH (an analog of harmine for MAO-A) and [18F]FAZIN3 (binds to MAO-A), we have compared MAO-A in anterior cingulate in AD and control (CN) subjects. Our preliminary findings show >100% increase of MAO-A in anterior cingulate in postmortem AD brain subjects, and this increase in MAO-A positively correlated with increases in Tau, Aβ and TSPO. This may suggest greater neurotransmitter breakdown, increased production of reactive oxygen species, potentially causing protein degradation, aggregation and inflammation in AD. In order to ascertain a role of MAO-A in AD and compliment current imaging approaches in understanding Aβ and NFT accumulation in AD, we propose to carry out a detailed postmortem study in AD subjects to confirm MAO-A upregulation. Our goal is to examine anterior cingulate and hippocampus in AD and CN subjects, two brain regions where MAO-A has been studied with [11C]Harmine. In addition to [18F]FAZIN3 and [18F]FEH, we will also use [3H]Harmine (chemically identical to [11C]Harmine, except for the radioisotope). Positive findings with [3H]Harmine will support and provide impetus for PET studies in AD using [11C]Harmine, without much delay, since it is already approved for human use. For the two brain regions, comparisons between the biomarkers will be carried out to support the hypothesis that MAO-A is upregulated in AD and positively correlated with Tau, Aβ and TSPO measures of the same subjects. Impact of our findings will support PET imaging studies of MAO-A in AD subjects and may have the potential for AD drug development of MAO-A inhibitors for therapeutic purposes.