Sid E. O'Bryant, Ph.D. - US grants

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a major public health issue facing the world's aging population; however, to date, there is no rapid and cost effective means for early diagnosis that is widely accessible. It has been suggested that a blood-based screening will become the first-step in the AD diagnostic process, although no such test currently exists. In our prior work through the Texas Alzheimer's Research & Care Consortium (TARCC), we created a serum-based screening algorithm that correctly classified 94% of those with and without AD. We then followed that work-up by creating a blood-based algorithm in the TARCC that worked across both serum and plasma that, when applied to the ADNI plasma samples, correctly classified 89% of those with and without AD in the entirely independent cohort. The long-term goal of this project is the validation of the our blood-based screening instrument for AD. The specific aims of the current project are as follows: Specific Aim 1: To test the reliability and validity of our previously created blood-based screening algorithm, and Specific Aim 2: To validate our blood-based algorithms against other diagnostic modalities (i.e., neuropathological findings and CSF analyses). Multiplex serum- and plasma-based biomarker assays (using electrochemiluminescence) will be conducted on 1,100 samples from the TARCC and Mayo Clinic Jacksonville biobanks. The establishment of a blood-based screening instrument for AD will significantly change the field of geriatric medicine. Such a tool would fit into the existing medical infrastructure as a frontline population-based screening device where positive findings can be followed-up with clinical, imaging or CSF assessments. This overall approach will increase accessibility to standard care far beyond what can be offered by other methodologies. This approach will also provide a more rapid and cost-efficient means for screening into AD clinical trials.

PROJECT SUMMARY It is our hypothesis that Alzheimer's disease (AD) and mild cognitive impairment (MCI) are heterogeneous conditions and, therefore, a paradigm shift is required to identify specific subpopulations for targeted interventions. This approach has generated significant success in other complex diseases such as cancer and cardiovascular disease. A key opportunity in this context is the identification of those most likely to benefit from non-steroidal anti-inflammatory (NSAID) drugs and other anti-inflammatory compounds. The relation between inflammation and the development of AD, MCI, and cognitive decline has received a great deal of attention with basic science and observational human studies demonstrating a protective effect against cognitive loss. Likewise, in our work, inflammation has been a key mechanism in the biological profile that is indicative of disease presence. Based on a wealth of literature (epidemiological, cross-sectional, pathobiological and animal model), multiple clinical trials have been conducted to determine the utility of NSAID compounds in treating or preventing AD (Alzheimer's Disease Cooperative Study [ADCS] AD and MCI anti-inflammatory trials; Alzheimer's Disease Anti-inflammatory Prevention Trial [ADAPT]); however, each of these studies failed to demonstrate therapeutic benefit, in fact some patients may have exhibited worsening cognitive performance with treatment. Our preliminary data suggests that particular subsets of patients in these trials did benefit from treatment and that our blood-based proinflammatory endophenotype can identify both positive and adverse responders within these trials. Here we propose to leverage three previously conducted clinical trials to test our hypothesis that our blood- based proinflammatory endophenotype can identify the subsets of patients who benefited from these previously conducted clinical trials. By conducting proteomic assays from existing biorepositories from the ADCS and ADAPT, we will address the following Specific Aims: Specific Aim 1. Demonstrate the utility of the proinflammatory endophenotype as a means for patient selection into NSAID therapy for treating and preventing AD; Specific Aim 2. To determine if change in proinflammatory endophenotype scores over time is a biomarker of therapeutic response. By leveraging a highly innovative method and substantial existing resources, the current project addresses a significant need in the search for novel approaches AD therapeutics. The significance of the current project is the identification of a specific subset of patients who will experience clinically significant cognitive benefit from administration of NSAID medication. If successful, the current project will set the stage for a novel clinical trial that enrolls patients specifically based on baseline proinflammatory endophenotype scores for administration of NSAID therapy. In the long-term, this line of research is designed to build a person-centered (i.e. personalized) approach to the treatment of Alzheimer's disease.

PROJECT SUMMARY The long-term goal of this research is to address two important health disparities faced by Mexican Americans suffering from Alzheimer's disease (AD) and mild cognitive impairment (MCI): (1) younger age of onset and (2) decreased access to early detection and treatment. AD is the most common form of neurodegenerative dementia and the 5th leading cause of death for those over 65 (8th leading cause of death for U.S. Hispanics). AD has an annual health care cost that is greater than that of cardiovascular disease (CVD) and cancer. While death rates from CVD and cancer have declined in recent decades, death rates have steadily increased for AD. The Mexican American elderly population is among the fastest growing segments of the population; however, little research on MCI and AD has been conducted among this underserved group. Here we will leverage our ongoing Health & Aging Brain among Latino Elders (HABLE) study to identify different pathways for MCI and AD among Mexican Americans, define subtle neuroanatomical and blood-based biomarker changes that are related to future risk of MCI and AD as well as provide evidence to support the utility of our AD blood-based detection tool that can be implemented in primary care settings. The current research team consists of leading experts in Mexican American cognitive aging, the epidemiology of MCI and AD as well as biomarkers of MCI and AD (neuroimaging and blood-based). The project will leverage a substantial existing infrastructure and HABLE cohort to address the two health disparities outlined above through the following specific aims: Specific Aim 1 - Examine the impact of higher rates of metabolic burden and depressive symptomatology on MCI and AD among community-dwelling Mexican Americans; Specific Aim 2 - Examine neuroimaging and blood-based biomarkers associated with MCI and AD among Mexican Americans; and Specific Aim 3: Validate our blood-based AD screening tool as the first-step in a multi-stage diagnostic process among Mexican Americans. The current project will address significant health disparities faced by Mexican American elders suffering from and at risk for MCI and AD. The identification of novel pathways related to disproportionate burden of diabetes and depression can lead to novel ethnic-specific interventions. The identification of a blood-based screening tool for AD will provide primary care providers a way of meeting the needs of a rapidly growing elderly Mexican American population.

PROJECT SUMMARY The Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (http://a4study.org/) is a ground-breaking study designed prevent cognitive decline among cognitively normal older adults who are amyloid positive. If successful, the A4 trial will demonstrate, for the first time, that it is possible to delay this devastating disease by initiating treatments prior to clinical manifestation. Such success would engender an effort to make treatments available globally. However, the only currently available means for screening older adults into potential trials (or regularity approved therapy) for amyloid-removing medications are amyloid PET scans or lumbar punctures (LPs), neither of which are viable options for large-scale screening. Here we propose to meet the objectives of PAR-15-359 by leveraging existing biorepository samples from the A4 trial. The long-term goal of this work is the establishment of a multi-tier neurodiagnostic approach for screening eligible older adults into clinical trials (and clinical intervention) of anti-amyloid agents to slow and/or prevent AD progression. The PIs are global leaders in blood-based biomarkers of AD. This project will leverage a substantial existing infrastructure to address the following Specific Aims: Aim 1: Validate our AD blood screen as the first step in screening cognitively normal older adults into prevention trials using anti-amyloid agents. Aim 2: Determine the accuracy of neuronally derived exosomes (NDEs) for screening cognitively normal older adults into prevention trials using anti-amyloid agents. Aim 3: Demonstrate the cost-benefit of a multi-tier screening process for enrollment into prevention studies of AD. The significance of the current proposal is the completion of the first-ever study of a blood-based Alzheimer's screening test as the first-step in a multi-tier screening process for prevention trials. The availability of such a process would increase access to both clinical trials and medications once FDA approved and provide a previously utilized strategy for reimbursement approval from other diseases.

PROJECT SUMMARY The long-term goal of this research is to address two important health disparities faced by Mexican Americans suffering from Alzheimer's disease (AD) and mild cognitive impairment (MCI): (1) younger age of onset and (2) decreased access to early detection and treatment. AD is the most common form of neurodegenerative dementia and the 5th leading cause of death for those over 65 (8th leading cause of death for U.S. Hispanics). AD has an annual health care cost that is greater than that of cardiovascular disease (CVD) and cancer. While death rates from CVD and cancer have declined in recent decades, death rates have steadily increased for AD. The Mexican American elderly population is among the fastest growing segments of the population; however, little research on MCI and AD has been conducted among this underserved group. Here we will leverage our ongoing Health & Aging Brain among Latino Elders (HABLE) study to identify different pathways for MCI and AD among Mexican Americans, define subtle neuroanatomical and blood-based biomarker changes that are related to future risk of MCI and AD as well as provide evidence to support the utility of our AD blood-based detection tool that can be implemented in primary care settings. The current research team consists of leading experts in Mexican American cognitive aging, the epidemiology of MCI and AD as well as biomarkers of MCI and AD (neuroimaging and blood-based). The project will leverage a substantial existing infrastructure and HABLE cohort to address the two health disparities outlined above through the following specific aims: Specific Aim 1 - Examine the impact of higher rates of metabolic burden and depressive symptomatology on MCI and AD among community-dwelling Mexican Americans; Specific Aim 2 - Examine neuroimaging and blood-based biomarkers associated with MCI and AD among Mexican Americans; and Specific Aim 3: Validate our blood-based AD screening tool as the first-step in a multi-stage diagnostic process among Mexican Americans. The current project will address significant health disparities faced by Mexican American elders suffering from and at risk for MCI and AD. The identification of novel pathways related to disproportionate burden of diabetes and depression can lead to novel ethnic-specific interventions. The identification of a blood-based screening tool for AD will provide primary care providers a way of meeting the needs of a rapidly growing elderly Mexican American population.

PROJECT SUMMARY A primary aim of PAR-15-359 ?Novel Approaches to Diagnosing Alzheimer's Disease & Predicting Progression? is to ?identify new biomarkers that are minimally invasive, inexpensive and that could be used for screening a general population.? Further, this PAR states that ?A biomarker that could be used for screening in primary-care settings would be particularly useful.? The Centers for Medicare & Medicaid Services (CMS) Annual Wellness Visit (AWV) includes a cognitive examination (CMS.gov); however, the 2015 Gerontological Society of American working group reported that ?older adults are inadequately assessed for cognitive impairment during routine visits with their primary care providers?. This report further states that without a diagnosis, individuals with AD do not ?benefit from post-diagnostic medical care? that can ?lead to improved health-related outcomes and well-being?. Here we propose the first-ever examination of an AD Blood Test as the first-step in this multi-tier diagnostic process beginning in primary care. The PIs are global experts in blood-based biomarkers of AD and longitudinal studies of AD. PI O'Bryant has followed the Institute of Medicine (IOM) guidelines for the development and validation of the AD Blood Test, which has been validated across cohorts, assay platforms, tissues type, animal models, and ethnicities. We will leverage a substantial existing infrastructure and resources to address the following Specific Aims: Aim 1: Validate the Alzheimer's Blood Test in Primary Care Settings; Aim 2: Validate the Alzheimer's Blood Test for the Detection of Prodromal AD in Primary Care Settings. The current proposal is highly significant for several reasons: (1) The AD Blood Test will provide primary care providers globally with a cost-effective means for detecting AD in routine clinical practice by selecting only those patients that require additional costly and invasive follow-up confirmatory diagnostic procedures; (2) The AD Blood Test will provide a means for reducing screening costs in prevention trials by over 50%; and finally (3) The AD Blood Test will provide a rapidly scalable means for increasing access to novel therapies globally once Regulatory approval is obtained.

PROJECT SUMMARY/ABSTRACT One of the most exciting recent advances in clinical neuroscience has been the establishment of a connection between sleep and Alzheimer's Disease and Related Dementias (ADRD). Patients with ADRD frequently experience poor sleep quality/disorders and growing evidence, including from our team, suggest that poor sleep quality increase risk of developing ADRD. This bidirectional association has profound implications for prevention and treatment, however many questions remain. Mexican Americans (MAs) represent the fastest growing ethnic group in the U.S. and MAs face numerous health disparities including greater metabolic/vascular risk compared to Non-Hispanic Whites (NHWs). Recent evidence, while controversial, suggests greater subjective sleep problems in Hispanics, but these data are lacking in older Hispanics, especially MAs, and little is known about objectively measured sleep. Our cost-efficient and innovative study will address many of these gaps. The overall objective of this proposal is to determine the association between sleep quality (objective and subjective measures) and cognitive impairment including ADRD among MAs and NHWs, and to elucidate targeted pathways linking these conditions. We will leverage the ongoing Health & Aging Brain among Latino Elders (HABLE) study to cost-efficiently investigate objectively measured sleep among 500 community-dwelling MAs and 500 NHWs across level of cognitive impairment (approximately 40% with Mild Cognitive Impairment/ADRD). The HABLE study has deep phenotyping and biomarkers for metabolic/vascular health. In addition, all participants will have a brain MRI and a subset will have amyloid PET scans, cost-efficiently enabling our investigation of neurodegenerative and vascular/inflammatory pathways associated with sleep quality. We propose to conduct these aims as part of the HABLE-Dormir ancillary study: 1) To characterize objective and subjective sleep quality among older NHWs and MAs across the cognitive spectrum, 2) To examine the longitudinal association between sleep quality and 2 to 3-year cognitive decline, 3) To determine the association between sleep quality and key mechanistic pathways including vascular and inflammation and 4) To investigate the association between sleep quality and biomarkers of amyloid (PET scans and plasma A?40 and A?42) and other measures of neurodegeneration (plasma tau, NFL, and hippocampal atrophy). We have an unprecedented opportunity, working with a very experienced and multidisciplinary team, to conduct the first-ever comprehensive investigation of several key pathways among MAs and NHWs that may link sleep and ADRD. Understanding the longitudinal association and mechanisms between sleep and ADRD among older MAs will help with the early detection and prevention of ADRD in this underserved population as well as all older adults.

PROJECT SUMMARY The 2018 NIA - Alzheimer's Association Research Framework [AT(N)] for Alzheimer's Disease (AD) provides a biological context for studying AD by incorporating state-of-the art biomarkers of amyloid (A), tau (T) and neurodegeneration (N). Despite the fact that these biomarkers vary by race/ethnicity, no prior work has systematically examined them among Mexican Americans. Given that (1) Hispanic/Latinos are projected to experience the largest growth in AD and Alzheimer's Disease Related Dementias (ADRDs) by 2060 and (2) Mexican Americans are the largest segment of the U.S. Hispanic/Latino population, there is a pressing need to study prevalence, progression and clinical impact of these biomarkers among this underrepresented group. This work addresses goals of the National Alzheimer's Project Act (NAPA), NIA Milestones for AD and ADRD research, and needs highlighted by the AT(N) framework publication. The current research team consists of leading experts in Mexican American cognitive aging, neuroimaging (PET and MRI), blood-based biomarkers as well as advanced statistical modeling. By leveraging the ongoing HABLE cohort, infrastructure and data, we will test the following Specific Aims: Aim 1: Examine the prevalence, progression and clinical impact of cerebral markers of the 2018 AT(N) framework among community-dwelling Mexican Americans. Aim 2. Examine the prevalence, progression and clinical impact of blood markers of the 2018 AT(N) framework among community-dwelling Mexican Americans. Aim 3: To determine if blood-based biomarkers of A?40, A?42, tau and NfL can be used to screen for AT(N)-defined preclinical AD, prodromal AD and AD dementia for enrollment of Mexican Americans into novel clinical trials. The current study is highly significant for several reasons: (1) This is the first-ever large-scale multi-ethnic study of the AT(N) biomarkers, which is of tremendous importance given the racial/ethnic make-up of the U.S. population; (2) this work directly addresses goals set forth by NAPA as well NIA-Milestones for AD/ADRD science; (3) it will determine if ethnic-specific biomarker trajectories are appropriate and finally, (4) it will generate data and methods for increasing enrollment of Hispanics into clinical trials across the AT(N)-defined spectrum of AD (primary, secondary and tertiary prevention) beginning in primary care settings.

PROJECT SUMMARY Currently, data collected and shared in the biorepository of our parent project HABLE continues to expand rapidly. Artificial Intelligence and Machine Learning (AI/ML) cannot make these data valuable to biomedical research until these data are AI/ML-ready. Therefore, there is an urgent need to develop effective AI/ML readiness for HABLE and other NIH-funded data-sharing projects. This proposal will focus on three critical and common areas to improve the AI/ML-readiness of data generated from our parent HABLE project: missing data imputation, feature selection and outlier removal, and data readiness report. We will address the following three specific aims: Aim 1) Develop a Machine Learning Based Multiple Imputation Method for Handling Missing Data; Aim 2) Develop a Recursive Feature Elimination and Cross-Validation (RFE-CV) Algorithm for Feature Selection and Outlier removal, and Aim 3) Develop an Integrated Tool to Report Data Readiness. The algorithms and tools from this application will be the first of their kind to report data readiness for NIH data- sharing projects to facilitate heterogeneous data and feature engineering for AI/ML. It will make data scientists improve their AI/ML modeling more effectively and effortlessly. The administrative supplement project will benefit not only the parent HABLE project but also all other NIH-funded data-sharing projects. We expect that with the development of the algorithms and tools we will complete high data readiness in the HABLE project, which will eventually make HABLE more innovative in developing state of the art methods for Alzheimer?s Disease (AD) clinical trials, leading to the development of effective personalized treatments which slow the progression of, and prevent, AD.

Omics Core Abstract The Omics Core (Core E), led by Drs. Sid O?Bryant and Mark Mapstone will use advanced methods to conduct state of the art quantitation of fluid-based biomarkers representing all levels of systems biology; from the genome to the metabolome for use in the proposed projects and to share with the broader scientific community. We will derive genomic, transcriptomic, proteomic, and metabolomic information from peripheral blood and cerebrospinal fluid (CSF) collected from our participants as part of our established clinical protocol. Peripheral blood is an accessible matrix with only minor risks associated with collection and would be preferred for translational applications, while CSF is a CNS-specific matrix with high specificity for CNS disorders like AD in DS. We will employ targeted approaches to quantify known markers from these matrices based on our preliminary work and we will use untargeted methods to quantify a variety of other potential markers. This combined approach will provide the highest likelihood of capturing the most valid and reliable fluid-based biomarkers and a rich dataset for new biomarker discovery by our group and other qualified groups around the world. The Core is represented by world class scientists with expertise in genomics and transcriptomics (Lee, Kamboh, Feingold, Cruchaga, Harari), epigenomics (Tycko), proteomics (O?Bryant, Fagan), and metabolomics (Mapstone, Cheema, Macciardi).

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.