This Phase I application targets PAS-19-316 to address the priorities for a) new, cost-effective, minimally-invasive biomarkers that could be used for screening and b) research that would identify new biomarkers that could serve as surrogate measures for disease progression in Alzheimer's Disease and Related Dementias (AD/ADRD). Specifically, Vivid Genomics is exploring the use of circular RNAs (circRNAs) in blood as a biomarker of AD and AD progression, including the possible identification of presymptomatic AD. The enormous public health challenge of AD is complicated by the lack of accessible, non-invasive tools for definitively diagnosing the disease prior to death. Although imaging and AD biomarkers in cerebrospinal fluid (CSF) can provide insight into disease status, they are not ideal for routine screening. Recently reported blood-based screens for amyloid b and phosphorylated tau (p-tau) represent a significant advance, but they require methods that are not easily scalable or may not have adequate sensitivity in early disease. In addition, they assess the presence of amyloid b and p-tau at a particular point in time and cannot currently be used to indicate the rate of disease progression or future likelihood of decline. Thus, developing new scalable, cost-effective, minimally-invasive blood-based biomarkers could provide a much-needed tool for routine screening in high-risk individuals, routine follow-up to track AD progression, or ongoing monitoring to assess treatment efficacy. Recent findings indicate several circRNAs differentially expressed in the brains of patients with and without AD are significantly associated with AD diagnosis, clinical severity, and neuropath logical severity. In addition, changes in circRNA expression can be detected even in presymptomatic patients. Preliminary studies indicate these markers are also differentially expressed in blood, providing a basis for exploring blood-based circRNAs asbiomarkers of AD and/or AD progression. In this proof-of-concept Phase I SBIR, Vivid proposes to identifymultiple circRNAs whose expression in blood is associated with AD diagnosis, clinical severity, and/or neuro-pathological severity. Aim. Identify blood-based circRNAs that are associated with AD status and AD-biomarker positivity. RNA-seq will be used to analyze circRNAs in blood from 300 patients in the Knight Alzheimer's Disease Research Center cohort. A rank-ordered list of circRNAs of interest will be developed basedon the strength of their association with AD traits adjusted for median transcript integrity score, age of onset, batch, sex, and genetic ancestry. Associations and rank order will then be validated in blood from 300 patients in the AD Neuroimaging Initiative (ADNI) cohort. Go/No-Go Criterion: Identify ⥠2 blood-based circRNAs correlated with one or more AD traits (FDR < 0.05). Impact-Proof-of-concept would provide a foundation for development of blood-based circRNAs as biomarkers of AD and/or AD progression. Validation and regulatory clearance would provide a scalable, cost-effective, minimally-invasive alternative to current biomarkers, which could support routine screening of high-risk individuals and inform treatment decisions and clinical trial designs.
Public Health Relevance Statement: PROJECT NARRATIVE Additional tools are needed to help clinicians diagnose Alzheimer's Disease and track its progression over time. This project is designed to advance the development of a new blood-based test that could allow clinicians to rapidly and inexpensively detect Alzheimer's Disease, perhaps even before symptoms appear, and it may allow them to track progression of the disease over time to inform treatment and patient planning.
Project Terms: 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, Blood, Blood Reticuloendothelial System, Brain, Brain Nervous System, Encephalon, Brain Pathology, Cerebrospinal Fluid, cerebral spinal fluid, spinal fluid, Clinical Trials, Cessation of life, Death, Diagnosis, Disease, Disorder, Foundations, Future, Immunoprecipitation, Immune Precipitation, Methods, Neurosciences, Patients, Public Health, Research, Saliva, Testing, Time, Universities, Washington, Work, circular RNA, closed circular RNA, 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, base, Blood specimen, Blood Sample, Clinical, Phase, Age of Onset, insight, Individual, Disease Progression, p-tau, p-Ï, phospho-tau, phospho-Ï, phosphorylated tau, tau-1, Collaborations, Therapeutic, Genetic, tool, Nature, machine learned, Machine Learning, Adopted, Severities, Pattern, interest, success, cohort, trait, neuro-imaging, neurological imaging, neuroimaging, novel, Reporting, Modeling, response, case-controlled, case control, Genomics, Address, Symptoms, Clinical Trials Design, Collection, Small Business Innovation Research Grant, SBIR, Small Business Innovation Research, Transcript, Validation, Pathologic, Monitor, sex, follow-up, Active Follow-up, active followup, follow up, followed up, followup, Development, developmental, Image, imaging, National Institute on Aging, National Institute of Aging, National Institute of Neurological Disorders and Stroke, NINDS, National Institute of Neurological Diseases and Stroke, predictive modeling, computer based prediction, prediction model, Advanced Development, design, designing, Treatment Efficacy, intervention efficacy, therapeutic efficacy, therapy efficacy, cost effective, commercialization, high risk, minimally invasive, routine practice, Biological Markers, bio-markers, biologic marker, biomarker, disease diagnosis, transcriptome sequencing, RNA Seq, RNA sequencing, RNAseq, screening, Genomic DNA, gDNA, differential expression, differentially expressed, transcriptional differences, blood-based biomarker, blood-based marker, recruit, routine screening, annual screening, 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, genetic testing, gene testing, gene-based testing, Alzheimer's disease diagnosis, Alzheimer's diagnosis
