Development of an ultrasensitive blood-based… (F32AG087642) – Project Grant to Brigham & Womens Hospital Inc.

Abstract: Alzheimer's disease (ad), prevalent among the elderly, is a fatal neurodegenerative disorder marked by memory deficits and cognitive decline. IT currently afflicts approximately 6.5 million americans with an estimated 500,000 new cases diagnosed annually. One challenge in improving ad treatment is delayed intervention, as ad develops years before symptoms are evident. Objective, accurate diagnosis of ad is critical for effective intervention but remains an unmet clinical need. Existing diagnoses involve either lengthy and subjective clinical tests with neuroimaging or expensive and invasive procedures like lumbar punctures. This work aims to engineer an ultrasensitive blood-based diagnostic tool that can accurately determine the presence and severity of ad, to inform effective treatment. The accuracy of blood tests is partly hampered by scarce presence of neurological proteins, as the blood-brain barrier (BBB) restricts their presence. Blood extracellular vesicles (EVS) can reflect protein profiles in inaccessible brains, as they can traverse the BBB. Utilizing markers in EVS improves accuracy and reliability of current blood tests. Yet, developing cost-effective, streamlined, and scalable EV isolation tools remains a challenge. Integrating analysis of novel and robust ad biomarkers in EVS may further enhance ad diagnosis. One such marker could be the collective phosphorylation changes in TAU, as an increase in TAU phosphorylation correlates with TAU aggregation. However, a highly selective and quantitative assessment of protein phosphorylation is lacking. The diagnostic challenge lies in the low concentrations of ad-specific biomarkers present in EVS, particularly the minute fraction of phosphorylated proteins. Therefore, the proposed diagnostic tool will utilize single molecule detection to measure low abundance ad protein biomarkers in EVS. Single molecule array (simoa) technology, developed by the walt lab, is the current state of the art for ultrasensitive protein detection, using digital enzyme-linked immunosorbent assay (elisa) to isolate and count single molecules in femtoliter-sized microwells, achieving 1000-fold higher sensitivity than conventional elisa. An integrated pipeline designed to efficiently isolate EVS from plasma and quantitatively uncover the phosphorylation state of ad diagnostic biomarkers is required to advance ad diagnosis. This pipeline can be achieved through multiplexed simoa assays developed for a panel of robust ad protein biomarkers, enabling a simple, accurate, minimally invasive, and cost-effective diagnostic tool for ad, using plasma EVS. This project will provide DR. Stephanie zhang rigorous scientific training for an independent academic research career. She will work closely with DR. David walt in a highly interdisciplinary, collaborative environment at brigham and women's hospital and the wyss institute, and develop an extensive skillset in analytical chemistry, diagnostics, and technology development and translation. The training plan also provides opportunities to expand her scientific expertise and professional skills through coursework, seminars, conferences, and grant writing workshops.

Action	Obligated	Date
Amendment	$78,220	Jun 25, 2025
Original award	$76,528	May 24, 2024

Development of an ultrasensitive blood-based diagnostic for alzheimer's disease

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