Project 3: Biomarkers for DS Clinical Trials

PROJECT 3 ABSTRACT Nearly all adults with Down syndrome (DS) will face the burden of Alzheimer's disease (AD) if they live to sufficient advanced age. Despite the billions of dollars expended on clinical trials targeting AD in the general population, there remains a dearth of trials targeting this devastating disease in adults with DS. The Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS) offers a unique opportunity to generate biomarkers to advance precision medicine based clinical trials targeting AD in in DS (DS-AD). Furthermore, the NIH INCLUDE Project explicitly sets the stage for novel therapies targeting this population. Project 1 will examine an AT(N) framework in DS, Project 2 will identify genomic markers associated with MCI-DS and DS-AD and Project 3 will translate all of this work into a novel precision medicine model to DS-AD, directly addressing Milestone 1.A under “Population Studies, Precision Medicine & Health Disparities” of the NIA AD & ADRD Milestones. The ABC-DS cohort undergoes detailed longitudinal assessments including medical and neuropsychological assessments, imaging (MRI, PET) and fluid (CSF and blood “omics”) biomarkers as outlined in the Cores. When possible, the Neuropathology Core will acquire brain tissues and neuropathology data. The current team has extensive experience advancing novel “omics” biomarkers for neurodegenerative diseases. In our prior work, we have generated blood-based biomarkers that are highly accurate in (1) detecting DS-AD and MCI-DS as well as (2) predicting future risk for the development of MCI and AD among adults with DS. In our work in AD in the general population, we have identified subgroups of patients and shown that these subgroups differentially respond to targeted therapeutics. Our preliminary data also show that subgroups exist among adults with DS. Here we will leverage the ABC-DS cohort to address the following Specific Aims: Aim 1: Generation of Diagnostic Biomarkers for Clinical Trial Enrichment for Delaying and Slowing AD in Adults with DS (COU 1: Diagnostic Biomarker); Aim 2: Characterization of Predictive Biomarkers for Clinical Trials for Delaying and Slowing AD in Adults with DS (COU 2: Predictive Biomarker); Aim 3: Generate Surrogate Biomarker Outcomes for Clinical Trials for Delaying and Slowing AD in Adults with DS (COU 3: Response Biomarker); Aim 4: Translate findings from Projects 1 and 2 into a precision medicine model for AD in DS. It is anticipated that findings from Projects 1 and 2 will inform the biomarkers above and, therefore, biomarkers and biomarker profiles identified in Projects 1 and 2 will be tested within the framework of Project 3. Project 3 is highly significant as it will (1) significantly advance a precision medicine approach to treating and delaying AD in DS as well as (2) provide a model for the creation and implementation of a precision medicine model for AD in the general population.