title: Blood-Based Oligomeric and Other Protein Variant Biomarkers to Facilitate Pre-Symptomatic Diagnosis and Staging of Alzheimer's Disease.
abstract: Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer's disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis. While the subsequent diagnoses for the cases covered several different conditions, all samples had elevated protein variant levels relative to the plasma controls although with different individual biomarker profiles. We then analyzed a set of longitudinal human plasma samples from four AD (encompassing time points prior to MCI diagnosis and continuing until after conversion to AD) and two control cases. Pre-MCI samples were characterized by high TDP-43 variant levels, MCI samples by high Aβ variant levels, and AD samples by high Aβ and tau variant levels. Sample time points ranged from ∼7 years pre-MCI to ∼9 years after AD conversion. Bivariate correlations showed a negative correlation with TDP-43 levels and positive correlations with cumulative Aβ and oligomeric tau levels indicating an increase in neurodegenerative processes with time in AD. Detection of disease related protein variants not only readily selects AD cases from controls, but also stages progression of AD and holds promise for a pre-symptomatic blood-based biomarker profile for AD.
authors.affiliation: Chemical Engineering, The School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Chemical Engineering, The School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Schulz
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.affiliation: Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.affiliation: Chemical Engineering, The School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sierks
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000150:complications / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000097:blood*; D058070:Asymptomatic Diseases; D003072:Cognition Disorders / Q000097:blood / Q000209:etiology; D004268:DNA-Binding Proteins / Q000097:blood*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016875:tau Proteins / Q000097:blood*
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D016875:tau Proteins
keywords: Alzheimer’s disease; TDP-43; amyloid-β; biomarkers; longitudinal; oligomers; plasma; sera; tau