Abstract

Exosomes as Liquid-Biopsies for Alzheimer’s Disease (AD)

Christina Coughlan, Assistant Professor, University of Colorado

An estimated 6.5 million Americans are living with Alzheimer’s disease (AD), a number that is expected to more than double by 2050. AD is the fifth leading cause of death among adults aged 65 and older, and the seventh leading cause of death among all adults. In 2021, the U.S. spent over $355 billion on AD/dementia, while 11 million Americans provided billions of hours of unpaid care for those affected. And yet, there remains no cure, and much information is still needed for us to more fully understand how AD pathology is initiated and propagated in a manner that results in neuro-degeneration, memory loss and death. To better understand AD in terms of its causes, progression and response to interventions, more sensitive and selective Biomarkers are essential. While CSF and Amyloid/Tau PET imaging, in research settings, are considered the gold standards for determining who with dementia is on the AD continuum, these approaches are both invasive and costly. If these become the most reliable diagnostic tools of the future, it will serve to further increase the chasm in health disparities as these tools are unavailable and unaffordable to many in our community. An additional challenge is that pathological changes related to AD begin up to 20 years before symptoms are evident, often leaving the medical community with the impossible task of reversing years of pathology at first diagnosis. While Amyloid and Tau PET imaging and CSF Biomarkers could provide earlier identifiers of high-risk individuals, their routine use is neither practical nor affordable in an already taxed healthcare system. In addition, their use in clinical trials to test preventative interventions to stave off AD neuropathological development and associated cognitive impairment also selects for Institutes with the funds to use these expensive assessments, preventing research that reflects a more diverse community when smaller research centers do not have access to these types of tools. Hence, plasma based, specific, sensitive and selective Biomarker measures that allow us to detect AD in its earliest stages are essential to improve both our understanding of the disease itself and our ability to determine the efficacy of interventions as they are developed. To address the existing deficiencies in accessible and affordable Biomarkers, the overarching aim of our work is is to use plasma exosomes as dynamic read-outs of cellular pathological changes so that AD onset and progression can be identified earlier, possibly preclinically, and the efficacy of therapeutic interventions determined. In our pilot study of 5 Control and 5 Mild Cognitively impaired (MCI) individuals (amyloid PET -ve and +ve respectively), our novel markers identified changes even at the earliest stages of AD. These tools are now being tested in larger cohorts to further test for the sensitivity and specificity of these Biomarkers. In addition, the approach utilized to develop these tools is now being applied to diseases that are in much need of early diagnostics such as pancreatic and ovarian cancer. Our hope if that we will develop more accessible and affordable tools for use in the clinic and in clinical research settings.