PROJECT SUMMARY/ABSTRACT Recent therapeutic drug trials in Alzheimer’s disease (AD) have failed to improve cognitive outcomes despite improvements on imaging-based targets (e.g., amyloid PET). One possible missing link is a failure to restore normal neuronal function. Measures of cortical excitability using transcranial magnetic stimulation with electroencephalography (TMS-EEG) have the potential to fill this gap by measuring the neuronal response to controlled perturbation. However, practical applications of TMS-EEG measures are currently limited by a dearth of data from brain regions involved in early-stage AD pathophysiology, and a lack of understanding of how cortical excitability is related to clinically useful metrics. The long-term goal of this project is to determine the extent to which cortical excitability is an important prognostic marker and/or treatment target in AD. This study assesses excitability in both motor cortex—a well-characterized TMS site—and parietal cortex—a brain involved in the early stages of AD pathogenesis. The objective of the present proposal is to understand how parietal cortical excitability is related to neuroimaging abnormalities and prognosis in a cohort of early-stage symptomatic AD participants (early AD). The hypothesis is that increased cortical excitability in parietal cortex is related to neurodegeneration, decreased network connectivity, and more rapid clinical decline. This will be tested with three independent Aims to assess how cortical excitability is related to 1) local cortical thickness, 2) resting state fMRI connectivity; and 3) disease progression. The proposed project is highly innovative, using TMS-EEG measures to capture local cortical excitability in AD, integrating neuroimaging and neurophysiologic measurements, and testing the extent to which cortical excitability predicts meaningful clinical outcomes. This contribution will be significant because it will inform our understanding of how measures of synaptic function are related to progression of AD pathology. Findings from this study will lay the groundwork for future clinical trials in AD seeking to measure restoration of neuronal function using novel biomarkers. The candidate has a strong commitment to a clinical research career in Alzheimer’s disease and related dementias. She is a practicing cognitive neurologist at Beth Israel Deaconess Medical Center and Instructor in Neurology at Harvard Medical School. Her training plan and research project are specifically designed to build her expertise in AD biomarkers, advanced neuroimaging techniques, and biostatistics for AD clinical trials. Her mentorship team, led by Dr. Daniel Press and Dr. Michael Fox, will provide critical guidance on the integration of TMS measures with neuroimaging. Additional mentorship will be provided by Dr. Mouhsin Shafi on TMS-EEG, Dr. Reisa Sperling on AD biomarkers, and Dr. Long Ngo on biostatistics. Completion of this five-year career development plan will ...