Phase I Amount
$1,040,019
This project will develop a multiplexed immunoassay for measuring patient-specific molecular profiles of the two protein markers of Alzheimer's disease (AD): amyloid beta (ABeta) and TAU from human cerebrospinal fluid (CSF). Both proteins are structurally complex due to the existence of multiple differentially cleaved forms (ABeta) and 6 isoforms containing 50+ phosphorylation sites (TAU). CSF provides a rich source of potential biomarkers, which can be extensively mined to build diagnostic and prognostic signatures of AD and AD-related dementias (ADRD) or to develop personalized patient profiles for drug discovery. At present, those efforts are constrained by the lack of technical capability to resolve multiple ABeta and TAU proteoforms, more specifically by the lack of products for multiplexed capture and enrichment of ABeta and TAU for quantitative mass spectrometry-based proteomics. This proposal seeks to build upon an earlier successful product development project performed by Adeptrix for a pharma customer. Using our BAMS platform, we were able to identify at least 14 novel low abundance CSF ABeta peptides and dramatically expand the sequence coverage of CSF TAU by adding two new types of probes, which complement the existing conventional probes for total (tTAU) and phospho-TAU (pTAU). The proposed immunoassay, termed ABeta/TauScan will address the current need of biologists, clinicians, and pharma for comprehensive molecular profiling tools for studying protein markers of neurodegeneration. Furthermore, it will open a path to developing similar assays for other protein targets, such as neurofilament light polypeptide (NFL) and alpha-synuclein. While ABeta/TauScan is intended primarily for CSF, post Phase II the reagents will be evaluated for use in serum/plasma. Throughout this project we will work closely with academic, clinical and industry partners to ensure the robust analytical performance of ABeta/TauScan. Once the assay is created, it will be validated by screening 300 CSF samples representing cognitively normal (CN) subjects, mild cognitive impairment (MCI) and AD subjects and establishing a molecular signature of CN to MCI to AD progression that will contain at least one novel marker for improved assay sensitivity and specificity.
Public Health Relevance Statement: NARRATIVE This project aims to develop a novel immunoassay for measuring molecular profiles of the two major biomarkers of Alzheimer's Disease: amyloid beta and TAU. The proposed immunoassay will allow biologists, clinicians and pharma researchers create more accurate diagnostic and prognostic signatures of various neurodegenerative diseases.
Project Terms: Age; ages; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Amino Acid Sequence; Primary Protein Structure; protein sequence; Epitopes; Antigenic Determinants; Binding Determinants; Biological Assay; Assay; Bioassay; Biologic Assays; Cerebrospinal Fluid; cerebral spinal fluid; spinal fluid; Complement; Complement Proteins; Digestion; Disease; Disorder; Human; Modern Man; Immunoassay; Light; Photoradiation; Methods; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nerve Degeneration; neurofilament; Patients; Peptides; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Proteins; Racial Group; Racial Stocks; Race; Reagent; Investigators; Researchers; Research Personnel; Sensitivity and Specificity; Software; Computer software; Specificity; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Mass Spectrum Analysis; Work; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Gender; Measures; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Clip; base; improved; Site; Clinical; Phase; Variant; Variation; Ensure; Individual; Recovery; Disease Progression; p-tau; p-Ï; phospho-tau; phospho-Ï; phosphorylated tau; tau-1; NAC precursor; PARK1 protein; PARK4 protein; SNCA; SNCA protein; a-syn; a-synuclein; alphaSP22; asyn; non A-beta component of AD amyloid; non A4 component of amyloid precursor; a-syn; a-synuclein; alpha synuclein; tool; Life; Complex; Source; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; Performance; Isoforms; Protein Isoforms; synthetic peptide; antibody conjugate; Pyroglutamate; novel; Reporting; Sampling; Proteomics; drug discovery; polypeptide; Address; Data; Molecular Fingerprinting; molecular profile; molecular signature; Molecular Profiling; Cognitive; Phosphorylation Site; Modification; N-terminal; NH2-terminal; C-terminal; combinatorial; abeta accumulation; abeta aggregation; amyloid beta accumulation; amyloid beta aggregation; amyloid ß accumulation; amyloid ß aggregation; aß accumulation; aß aggregation; progression marker; progression biomarker; novel marker; new marker; novel biomarker; product development; industry partner; industrial partnership; industry partnership; biobank; biorepository; screening; mild cognitive impairment; mild cognitive disorder; potential biomarker; potential biological marker; specific biomarkers; protein biomarkers; protein markers; profiles in patients; patient profile; prognostic signature; prognostic profile; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; Alzheimer's disease biomarker; Alzheimer's biomarker; Alzheimer's disease biological marker; Alzheimer's biological marker; detection limit; accurate diagnostics; diagnostic signature; diagnostic profile
