Longitudinal Blood-based Transcriptomic Changes in AD: Relation to Clinical and Biomarker Data

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ABSTRACT 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.