With an effective treatment yet to be developed, early detection and surveillance of disease progression for Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRD) are critical for the management and intervention of AD/ADRD. The recent accelerated approval of the new monoclonal antibody drug targeting amyloid-β, Aducanumab®, by FDA, which is likely more efficacious when treating properly stratified patients, highlighted the urgent clinical need for early and biomarker-specific diagnosis of AD. Current clinical practices with AD biomarker targeted positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) sample based proteomics analysis are not desirable point-of-care (POC) solutions for early detection due to the limited availability and accessibility of imaging facilities or invasive lumbar puncture for CSF collection. Given the advantages of non-invasiveness, cost effectiveness and easy access in general clinical settings, blood-based AD biomarker detections are more applicable POC diagnostic tools for early diagnosis of AD/ADRD. While two platforms, i.e., PrecivityADTM for Aβ40/Aβ42 detection and Simoa® for phospho-tau 181 (p-tau181), were recently granted FDA Breakthrough Device designations for clinical uses, both systems require highly specialized high-end instruments for sample testing, limiting their wide availability, particularly in the communities and regions with low or limited resources and health disparity. Furthermore, PrecivityADTM and Simoa® use antibody-coated magnetic beads to capture targeted AD biomarkers. However, the non-specific adsorption of serum proteins on the surface of beads forms a protein corona that can block the antibody from capturing biomarkers. In this SBIR Phase I project, we aim to develop a multiplexed AD biomarker detection platform that can integrate two innovative technologies, i.e., ultramagnetic iron oxide nanorods (IONRs) and anti-biofouling polymer coating for IONRs, for multiplexing six AD biomarkers in blood samples. The IONRs provide as strong magnetism as the magnetic beads used in PrecivityADTM and Simoa®, and also function as nano-stirring-bars to improve sample mixing, under an alternating electromagnetic field, for more efficient biomarker capturing. The anti-biofouling coating minimizes non-specific serum protein adsorption on IONRs to preserve the antibody affinity for targeted biomarkers in blood samples. The Phase I project will focus on (1) developing a prototype device enabling efficient blood sample mixing with anti-biofouling IONRs and multiplexed detection of six AD biomarkers, i.e., Aβ40, Aβ42, total-tau (t-tau), p-tau181, amyloid precursor protein (APP669-711), and neurofilament light protein (NfL), and (2) testing the developed system and evaluate its performance using the patient samples, followed by comparing and correlating the results with clinical diagnosis and imaging findings of the same patients. If successful, the device, to be further assessed by large-scale tests in Phase II, will provide a robust and cost-effective POC detection for screening and detecting AD in individuals at risk as well as surveilling the progression and treatment response for patients.
Public Health Relevance Statement: A cost-effective and accessible point-of-care (POC) test for detecting Alzheimer's disease (AD) at early or even pre-symptomatic stages is highly desirable, particularly in communities and regions with low or limited resources and health disparities. The goal of this Phase I SBIR project is to develop a prototype device for multiplexing six AD biomarkers in a POC blood-based test for early diagnosis and surveillance of AD. The successful development of the prototype device will enable a low-cost and easy-access POC blood-based test for AD screening and monitoring treatment response, which will be further assess in large-scale in the Phase II project.
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