Discovering Centrally Linked Peripheral Molecular Signatures of Alzheimer's Disease

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SUMMARY ABSTRACT 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 post- mortem 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 multi- ethnic 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.