SBIR-STTR Award

Our objective is to develop a blood-based diagnostic for Pre-symptomatic detection of Alzheimer's disease(AD) based on a Multiparameter Profiling (PreAMP).Currently there are over 18 million cases of AD worldwide, with the number of cases expected to nearly doubleover the next 15 years. In the US alone, total economic costs are estimated at nearly $200 billion per year1.Diagnosis is complex, costly and time-consuming. In part because of the lack of diagnostic tools and becauseAD represents a continuum of neurodegenerative disorders that share overlapping symptoms and proteinpathologies. For these reasons, ~58% of dementia is thought to be undiagnosed altogether, which result thatmany patients do not receive adequate, timely care or treatment2. Recent work has revealed that forms of theaggregated proteins commonly found in the brains of AD patients can also be detected in the blood, showingpromise for the development of a blood-based diagnostic. So far, however, different studies have emphasizedsingle markers over a multiparameter approach, with no consensus as to which marker is superior3-9.Therefore, a multiparameter biomarker assay may prove to be extremely valuable for early diagnosis of adiverse range of patients against a continuum of dementias.The vast majority of biomarker efforts have focused on detection of non-toxic variants rather than the actualtoxic aggregated protein species involved in neurodegeneration. Recently, our project team has developednovel biopanning technologies that enabled us to generate single chain antibody variable domain antibodies(scFvs) that bind to disease-specific variants of four key neuronal proteins implicated in AD and RelatedDementias (ADRD): tau, Aβ, TDP-43, and α-syn. Our scFvs react only to the variants found in brain andplasma samples from ADRD patients but not cognitively normal controls10-12. Levels of Aβ and TDP-43oligomers recognized by four of our scFvs were significantly elevated years before an initial diagnosis of mildcognitive impairment (MCI)9. During disease progression, we found that biomarker profiles change, so ourantibody-based diagnostic could also be used to stage progression of AD from pre-symptomatic through latestage, permitting clinical stratification of patients to support experimental therapy decision-making for ADRD9.Building from this work, this proposal is designed to develop a blood-based diagnostic for AD called PreAMP.The specific aims are to: 1) develop a low-volume, multiplex antibody assay for quantitation of plasma proteinvariants. 2) determine the optimal biomarker set for pre-symptomatic diagnosis of AD, 3) validate the assayperformance in a blinded retrospective study of longitudinal AD patient samples. Project Narrative Alzheimer's Disease affects millions of Americans. Inadequate methods for early-stage diagnosis have contributed to the poor characterization of patient subgroups, hindering the interpretation of therapeutic clinical trials and leaving caregivers without a clear understanding of the likely progression of the disease. This project will develop a multiparameter blood test for early detection of Alzheimer's Disease. Affect ; 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 ; Antibodies ; Autopsy ; necropsy ; postmortem ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Brain ; Brain Nervous System ; Encephalon ; Decision Making ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Goals ; Health ; Blood Tests ; Hematologic Tests ; Hematological Tests ; Hematology Testing ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunoassay ; Immunoglobulin Fragments ; Antibody Fragments ; Light ; Photoradiation ; Longitudinal Studies ; long-term study ; longitudinal outcome studies ; longterm study ; Methods ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; neurofilament ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Pain ; Painful ; Pathology ; Patients ; Physical Examination ; Medical Inspection ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Plasma Proteins ; Production ; Proteins ; Research ; Research Institute ; Retrospective Studies ; Sensitivity and Specificity ; Standardization ; Technology ; Testing ; Time ; 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 β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Measures ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; τ Proteins ; Treatment outcome ; Caregivers ; Care Givers ; Diagnostic tests ; Data Set ; Dataset ; Blinded ; Caring ; base ; Procedures ; Brain imaging ; brain visualization ; Phase ; Variant ; Variation ; Training ; Disease Progression ; tau-1 ; p-tau ; p-τ ; phospho-tau ; phospho-τ ; phosphorylated tau ; alpha synuclein ; NAC precursor ; PARK1 protein ; PARK4 protein ; SNCA ; SNCA protein ; a-syn ; a-synuclein ; alphaSP22 ; non A-beta component of AD amyloid ; non A4 component of amyloid precursor ; α-syn ; α-synuclein ; TAR DNA-binding protein 43 ; TDP-43 ; TDP43 ; protein TDP43 ; protein TDP-43 ; tool ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Diagnostic ; sun ; The Sun ; Consensus ; Complex ; Source ; Amentia ; Dementia ; 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 ; Clinical stratification ; Alzheimer's disease related dementia ; AD related dementia ; ADRD ; Alzheimer related dementia ; American ; early detection ; Early Diagnosis ; Performance ; novel ; economic cost ; validation studies ; Position ; Positioning Attribute ; Modeling ; Sampling ; performance tests ; assay development ; depository ; repository ; Experimental Therapies ; Investigational Treatments ; experimental therapeutic agents ; experimental therapeutics ; Investigational Therapies ; Molecular Interaction ; Binding ; Length ; Symptoms ; Detection ; Therapeutic Clinical Trial ; Cognitive ; Collection ; Pathologic ; Nutritional ; nutritious ; Development ; developmental ; cost ; design ; designing ; protein aggregation ; insoluble aggregate ; protein aggregate ; Consumption ; N-terminal ; NH2-terminal ; Alzheimer disease detection ; AD detection ; Alzheimer's detection ; stem ; aging population ; aged population ; population aging ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; mild cognitive impairment ; mild cognitive disorder ; cognitive testing ; cognitive assessment ; patient stratification ; stratified patient ; biomarker panel ; marker panel ; ineffective therapies ; ineffective treatment ; patient subsets ; patient subgroups ; patient subpopulations ; patient subtypes ; Amyloid beta-42 ; A β-42 ; A β42 ; A-beta 42 ; A-beta42 ; Abeta-42 ; Abeta42 ; Amyloid beta42 ; Amyloid β-42 ; Amyloid β42 ; Amyloidβ-42 ; Amyloidβ42 ; Aβ-42 ; Aβ42 ; Alzheimer's disease diagnosis ; Alzheimer's diagnosis ; Alzheimer's disease blood test ; Alzheimer's blood test ; Alzheimer's disease patient ; Alzheimer's patient ; Alzheimer's disease brain ; Alzheimer's brain ; cost estimate ; cost estimation ; antibody diagnostic ; antibody based diagnostic ; Alzheimer's disease diagnostic ; AD diagnostic ; Alzheimer's diagnostic ;

Our objective is to develop a blood-based diagnostic for Pre-symptomatic detection of Alzheimer's disease(AD) based on a Multiparameter Profiling (PreAMP).Currently there are over 18 million cases of AD worldwide, with the number of cases expected to nearly doubleover the next 15 years. In the US alone, total economic costs are estimated at nearly $200 billion per year1.Diagnosis is complex, costly and time-consuming. In part because of the lack of diagnostic tools and becauseAD represents a continuum of neurodegenerative disorders that share overlapping symptoms and proteinpathologies. For these reasons, ~58% of dementia is thought to be undiagnosed altogether, which result thatmany patients do not receive adequate, timely care or treatment2. Recent work has revealed that forms of theaggregated proteins commonly found in the brains of AD patients can also be detected in the blood, showingpromise for the development of a blood-based diagnostic. So far, however, different studies have emphasizedsingle markers over a multiparameter approach, with no consensus as to which marker is superior3-9.Therefore, a multiparameter biomarker assay may prove to be extremely valuable for early diagnosis of adiverse range of patients against a continuum of dementias.The vast majority of biomarker efforts have focused on detection of non-toxic variants rather than the actualtoxic aggregated protein species involved in neurodegeneration. Recently, our project team has developednovel biopanning technologies that enabled us to generate single chain antibody variable domain antibodies(scFvs) that bind to disease-specific variants of four key neuronal proteins implicated in AD and RelatedDementias (ADRD): tau, Aβ, TDP-43, and α-syn. Our scFvs react only to the variants found in brain andplasma samples from ADRD patients but not cognitively normal controls10-12. Levels of Aβ and TDP-43oligomers recognized by four of our scFvs were significantly elevated years before an initial diagnosis of mildcognitive impairment (MCI)9. During disease progression, we found that biomarker profiles change, so ourantibody-based diagnostic could also be used to stage progression of AD from pre-symptomatic through latestage, permitting clinical stratification of patients to support experimental therapy decision-making for ADRD9.Building from this work, this proposal is designed to develop a blood-based diagnostic for AD called PreAMP.The specific aims are to: 1) develop a low-volume, multiplex antibody assay for quantitation of plasma proteinvariants. 2) determine the optimal biomarker set for pre-symptomatic diagnosis of AD, 3) validate the assayperformance in a blinded retrospective study of longitudinal AD patient samples.

Public Health Relevance Statement:
Project Narrative Alzheimer's Disease affects millions of Americans. Inadequate methods for early-stage diagnosis have contributed to the poor characterization of patient subgroups, hindering the interpretation of therapeutic clinical trials and leaving caregivers without a clear understanding of the likely progression of the disease. This project will develop a multiparameter blood test for early detection of Alzheimer's Disease.

Project Terms:
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