Project Summary/Abstract If no preventative measures are developed, the number of individuals suffering from Alzheimer’s Disease (AD) is expected to triple by 2050; many of whom will be members of a minority group. Ethnic and racial disparities in Alzheimer’s disease exist; however, these disparities are severely understudied, especially amongst African Americans. The consequent need for less invasive and more cost-effective tools to identify stages of AD at an earlier and perhaps more treatable time-point has fueled research into plasma biomarkers. Neural (NDEs) and astrocyte-derived exosomes (ADEs) have demonstrated biomarker potential for detecting stages of AD and predicting the conversion of MCI to AD. Although the field has been focused on NDEs and ADEs, there are surprisingly no published reports demonstrating the biomarker potential of microglial derived exosomes (MDEs). Any potential value of plasma exosome cargo to accurately identify stages of MCI and predict the conversion of MCI to AD, will require additional validation studies that specifically account for ethnic and racial differences amongst its patient cohorts. Understanding how ethnic and racial factors modify AD risk can yield new insights into race-dependent biological mechanisms, which in turn, can inform future diagnostic and therapeutic interventions. With the existing infrastructure at my home institution (UCSD), reagents and combined expertise of my mentor and collaborators, I will use a multidisciplinary approach to accomplish my research objectives. In the mentored phase of this proposal, I will be trained in unbiased, Mass spectrometry (MS)-based proteomic profiling for novel biomarker identification. My mentored studies will also involve the purification and characterization of MDEs. Lastly, I will also use these samples to study the diagnostic and prognostic utility of ADE and MDE cargo proteins (e.g. Aβ and p-tau) to predict conversion of MCI to AD. During the independent phase, I will apply the methods and perspectives learned in the mentored phase of this application to cross-validate the biomarker potential of plasma exosomes in a live cohort of African American patients who are at risk for developing AD. Successful completion of this study will significantly advance the field of exosome biology in neurodegeneration and may lead to the identification of novel biological targets for therapeutic development of AD. The training and mentorship that I will receive because of this funding award will undoubtedly contribute to my productivity as an independent scientist. Moreover, the K99/R00 mechanism will provide with the support necessary to advance of establishing an NIH- R01 funded, independent laboratory where I plan to continue my studies in racial disparities, exosome biology and biomarker discovery.

PROJECT NARRATIVE Understanding how ethnic and racial factors modify Alzheimer’s disease risk can yield new insights into race- dependent biological mechanisms which in turn can inform future diagnostic and therapeutic interventions. An unbiased proteomic approach will be employed to examine the diagnostic and prognostic ability of plasma exosomes as biomarkers for AD. Successful completion of this study will significantly advance the field of exosome biology in neurodegeneration and may lead to the identification of novel biological targets for therapeutic development of Alzheimer’s disease.