Alzheimer?s disease (AD) is a complex and heterogenous condition in which multiple molecular pathways are disrupted in different cell-types and lead to disease. Genetic findings indicate that amyloid-beta protein clearance and degradation pathways, cholesterol metabolism and the immune system are associated with AD etiology. However, the specific mechanism, genes and molecular networks have not yet been completely identified. Single-nuclei transcriptomic (snRNA-seq) data from human brains provides a detailed molecular atlas to study the pathways dysregulated in AD. We propose to deepen our understanding of the genes, network and molecular pathways associated with AD by sequencing a high-number of neuronal and glial cells (approximately 3.3 million cells) from human brain carriers of key genetic mutations and high risk variants, non-carrier sporadic AD cases and neuropath-free controls. We will leverage a unique collection of human tissue from the Dominantly Inherited Alzheimer Network and Knight-ADRC brain banks, and select +220 brains to perform systematic cell- type specific transcriptomic analyses. This is a unique and innovative study designed to analyze cell-specific transcriptomic dysregulation in carriers of high effect risk variants (TREM2 and APOE) and fully penetrant pathogenic mutations in APP/PSEN1/PSEN2 and by comparing them to sporadic AD cases and neuropath-free controls. This is a powerful approach to address disease heterogeneity, and will provide highly informative insights into the biology and pathology of neurodegeneration. Replication of these findings will be performed in snRNA-seq data from induced pluripotent stem cell derived neurons, astrocytes, and microglia-like cells that will be genome edited to add/remove genetic variants, as well as datasets that are being publicly released. Finally, we will create a knowledge portal in which all of the processed snRNA-seq data from our study will be harmonized with that of other research groups to provide a comprehensive molecular atlas that will provide additional insights into the biology and pathology of AD for the entire research community.

Public Health Relevance

Alzheimer's disease (AD) is the most common neurodegenerative disease, but currently there is no effective means of prevention or treatment. Genetic mutations and risk variants provide support to the amyloid cascade hypothesis, cholesterol metabolism and immune response in the etiology of AD. In this project, we will generate a detailed molecular atlas of AD brains carriers of pathogenic mutations, risk variants, non-carrier AD, and neuropath-free controls to determine the specific pathways and molecular networks disrupted in the distinct brain cell-types that lead to AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
High Priority, Short Term Project Award (R56)
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Molecular Neurogenetics Study Section (MNG)
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Miller, Marilyn
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Washington University
Schools of Medicine
Saint Louis
United States
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