Project 1
Discovering Alzheimer’s disease (AD) biomarkers for early diagnosis, tracking of disease progression and timely therapeutic interventions is a significant need. Despite the utility of existing neuroimaging and cerebrospinal fluid biomarkers, there is an urgent need to develop cost-effective and blood-based biomarkers to apply at the population level. Large-scale multi-omics studies identified a multitude of molecular perturbations in AD. These discoveries support the rationale for discovery of peripheral biomarkers that capture the full spectrum of central changes that occur in this disease. Our proposal aims to leverage combined blood and brain multi-omics data in well-characterized cohorts to identify peripheral molecular signatures which reflect the central molecular perturbations that occur in AD brains. We hypothesize that blood molecular signatures can serve as centrally linked peripheral biomarkers (CLPBM) since many brain multi-omics changes can also be observed in blood and vice versa. As they are linked with brain molecular perturbations, such CLPBM can provide mechanistic information on potential drivers of disease and its progression. CLPBM can also be expected to aid in patient stratification according to biological subtypes and disease stage, ultimately paving the way for personalized medicine. There are, however, no sizable studies that simultaneously analyze brain and blood samples from the same individuals to discover centrally-linked peripheral molecular signatures (CLPMS) that can serve as future centrally-linked peripheral biomarkers (CLPBM). In Project 1, we leverage three studies with complementary strengths, Mayo Clinic Study of Aging, Alzheimer’s Disease Neuroimaging Initiative and Mayo Clinic Florida postmortem African American and Latino American cohorts, to accomplish our specific aims to: 1. Discover brain region-specific CLPMS through molecular profiling (transcriptome, genome, methylome, proteome, metabolome/lipidome) in up to 5 brain regions and in matched blood samples. 2. Identify cell-type specific CLPMS through single nucleus transcriptome profiling across 5 brain regions and in matched blood samples. 3. Establish CLPMS in diverse populations by profiling of same -omics measures across the same brain regions from LA and AA participants. 4. Discover CLPMS that reflect biological subtypes and temporal progression of AD through use of advanced analytics approaches of the molecular data. We expect to identify brain region and cell-type specific CLPMS, which reflect the heterogeneous neuropathology in AD; associate with or drive antemortem clinical, neuroimaging and cognitive progression and outcomes of AD; define biological subtypes and predict molecular stage of AD in multi-ethnic populations. Findings from Project 1, together with those from Projects 2 and 3, collectively comprising >20,000 multi-omics and >48,000 AD phenotypes from >3,700 multiethnic participants will be analyzed applying our well-defined Roadmap to Translation approach to prioritize CLPMS for translation to precision medicine biomarkers for AD. Further, the data, outcomes and knowledge from this Project will be shared broadly and serve as an unprecedented resource for the research community.
Project 2
Alzheimer’s disease (AD) is a progressive neurodegenerative condition leading to dementia. Despite intensive efforts, there are no disease modifying therapies proven to arrest or slow the course. Numerous clinical trials have failed due to incomplete understanding of pathophysiology, patient heterogeneity, and lack of precision in selection strategies based on stage and other features for which widely accessible predictive biomarkers would have a major impact. The overall goal of the U19 is to identify and validate Centrally-linked Longitudinal pEripheral biomARkers of AD (CLEAR-AD) in multi-ethnic populations by integrating longitudinal multi-omics and multimodal imaging and fluid endophenotypes from multiple independent cohorts. Project 2 will conduct the first longitudinal blood-based multi-omics study of the well-characterized ADNI cohort including 4,120 biospecimens and up to 7 time points. ADNI is the only cohort study to our knowledge with whole genome sequencing, longitudinal DNA and RNA samples, DNA methylation, metabolomics/lipidomics profiling and proteomics, along with longitudinal multimodal neuroimaging, and fluid AD biomarkers on the same participants. Based on our preliminary results, we hypothesize that we will be able to identify the relationship between longitudinal molecular signature changes and longitudinal “A/T/N/V” (amyloid, tau, neurodegeneration, and cerebrovascular) biomarker changes including network alterations in brain connectivity. The overarching goal of Project 2 is to identify novel, non-invasive, centrally-linked molecular signatures that can serve as candidate biomarkers suitable for early detection and design of tailored therapeutics supporting the future precision medicine of AD/ADRD. A 3-Tier approach will 1) test 4 hypothesized biological pathways (immune, vascular, myelination, synaptic integrity), 2) assess 20 additional ADRD pathways, and 3) discover novel molecular signatures using an unbiased search and Artificial Intelligence (AI) strategies. Aim 1 is to identify molecular signatures in peripheral blood associated with changes in cognitive status, both cross-sectionally and longitudinally. Aim 2 will identify molecular signatures in blood associated with changes in A/T/N/V AD biomarkers, both cross-sectionally and longitudinally. Aim 3 will assess the ability of multi-omics based molecular profiling at baseline and over time to predict future disease progression. Aim 4 will replicate and validate ADNI findings using blood- and brain tissue-based data (with Project 1) and data from multiethnic populations including African- and Latino- American ancestry (with Project 3). Project 2 will employ an integrative translational approach supported by the U19 Cores, combining longitudinal clinical, multi-omics, and AD biomarker data, including advanced neuroimaging, to enable deeper mechanistic insights into the molecular basis of AD and to identify new potential therapeutic targets and biomarker strategies. These outcomes directly support the NIA/NAPA goal of precision medicine for AD/ADRD.
Project 3
Despite a higher prevalence of Alzheimer’s disease (AD) among African Americans (AA) and Latino Americans (LA) compared to non-Hispanic whites (NHW), these populations remain underrepresented in AD biomedical research, particularly in biomarker studies and clinical trials. The overarching goal of Project 3 of this U19 is to leverage existing “trial-ready” AA and LA cohorts with longitudinal blood collections, clinical, neuroimaging and cognitive data in order to identify centrally-linked peripheral molecular signatures (CLPMS) that may serve as novel blood biomarkers that will improve diagnosis and the development of treatments in these underserved and understudied populations. Based on preliminary data from our group and others, we hypothesize that genetic variation, transcriptomic and epigenetic changes predisposing to dementia risk in AA and LA will reveal novel mechanisms associated with disease, as well as similarities with those identified in NHW. Project 3 will leverage existing AA and LA samples and data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, 66 AA 59 LA) and five Alzheimer’s Disease research Centers (ADRCs, 564 AA, 219 LA): Mayo Clinic, Indiana, 1Florida, Michigan and Knight ADRCs, plus an additional 300 AA and LA projected participants from these ADRC. Data from a sixth ADRC (Emory) collected from another 300 AA participants will also be incorporated. This project aims to: (1) identify blood multi-omic CLPMS in AA and LA that will improve AD diagnosis by effectively discriminating, with high specificity and sensitivity, between individuals clinically diagnosed with AD and who have amyloid, tau, neurodegeneration and vascular endophenotype changes characteristic of AD based on neuroimaging/CSF/plasma biomarker data, versus those who do not have these endophenotype changes characteristic of AD; (2) identify blood CLPMS that can predict the development, and that track with progression of AD, by analyzing longitudinal blood multi-omics data-matched to clinical, neuroimaging, neuropsychometric data from cognitively unimpaired, mild cognitive impairment and AD patients; (3) identify blood CLPMS that are specific to these populations, based on genetic variants, transcripts or epigenetic changes that may impact the development of AD, differentially in AA and LA vs. those of NHW ancestry (by comparison to findings from Project 2); (4) to determine if these blood CLPMS exhibit similar patterns in the brain (by comparison to findings from Project 1); (5) to determine novel pathways, genes and genetic variants involved in AD by using results from these multi-omics signatures identified in this project. Using a 3-tiered approach to analyze our findings and Roadmap to Translation to prioritize them, we expect to identify CLPMS in AA and LA in a comparative fashion with NHWs and will enhance knowledge on biomarker research, thus enabling precision medicine in these underrepresented populations. These studies will integrate information expected to also lead to better informed designs for therapies and possibly preventive interventions that are tailored to these populations.