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: <7S Gamma Globulin>