Understanding the structural, functional, and prognostic implications of cortical excitability in Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the leading cause of dementia and is increasing worldwide, yet currently lacks effective disease-modifying treatments. 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. 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 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 disease progression in AD. 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 and an excellent mentorship team including Dr. Press, Dr. Fox, Dr. Shafi, and Dr. Sperling. Her funded 5-year K23 project supports her career development by building expertise in AD biomarkers, advanced neuroimaging techniques, and biostatistics for clinical trials. However, in the first year of her K23 the candidate experienced the birth of her first child on 10/25/2021 and took a 3-month leave of absence. This Supplemental Award will offset delays in participant recruitment and planned coursework related to her leave of absence. The Award will also help the candidate overcome challenges in research productivity during the upcoming year due to increased family responsibilities. Specifically, this Award will speed up participant recruitment and data analysis and increase the pace of manuscript submission. This will allow the candidate to return to full productivity by the end of the 1-year supplemental period and build the foundation for her to apply for independent funding from an R01 by Year 4 of her K23. This Supplemental Award will be integral to the candidate’s ongoing career development as she launches a career as an independent investigator using novel neurophysiologic tools to advance prognosis and treatment of AD.