ABSTRACT (OVERALL) Our understanding of the neuropathology in Alzheimer’s disease is crude and largely centered on characteristic deposition of a few pathological proteins. Catalyzed by the BRAIN Initiative, a new generation of molecular tools to characterize the transcriptome, epigenome and spatial organization of single cells in complex brain tissues is rapidly revolutionizing our understanding of the diversity of cell types and their selective genetic profiles. These tools are applicable to postmortem human brain tissues and promise to expand our understanding of the core cellular and molecular correlates and mechanisms underlying Alzheimer’s disease. The goal of the proposed Center is to bring together experts in Alzheimer’s disease research and large-scale molecular/anatomical brain mapping to modernize Alzheimer’s disease tissue banking methods, and to combine traditional and quantitative neuropathology with emerging single nucleus transcriptomics, single nucleus epigenomics and spatial transcriptomics technologies. Applied to clinically typical Alzheimer’s cases of varying severity in an iterative and adaptive design, these techniques are expected to identify increasingly refined molecular pathways associated with specific neuronal and non-neuronal cell types and yield valuable insights into cell-type selective vulnerability or resistance to pathology. This increased resolution of AD pathology in terms of cell types and molecular pathways should provide mechanistic insights and hypotheses on disease initiation and progression, which we aim to use to catalyze the AD research community through the creation of an open access data resource linked with other large-scale brain mapping efforts. This Center framework is designed to be extensible to additional data modalities and technological advances as well as broader cohorts representing Alzheimer’s disease subtypes and Alzheimer’s disease related disorders in the future.

PROJECT NARRATIVE (OVERALL) New tools for detailed molecular and spatial analysis of single cells are revolutionizing our understanding of the brain, but characterization of neuropathology in Alzheimer’s disease has been limited primarily to histology and tissue-level analyses. The current proposal aims to improve Alzheimer’s disease brain tissue banking and analysis, and adapt single cell transcriptomic, epigenomic and molecular spatial analysis methods developed under the BRAIN Initiative and the Allen Institute for Brain Science to Alzheimer’s disease in human postmortem tissues. These tools will be applied in an iterative and adaptive fashion to generate an increasingly refined foundational understanding of the molecular and structural progression of AD, identify transcriptional and spatial hallmarks of early AD pathology and affected molecular pathways, and create a catalytic open access dataset for the research community.