Spatial analysis of regional, cell type and molecular hallmarks of Alzheimer's disease and comorbid dementias.

Allen Institute, Seattle WA

Investigators

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Abstract

ABSTRACT (PROJECT 3) Recent advances in highly multiplexed spatial genomics methods now allow extremely high-resolution characterization of cellular diversity in healthy brain tissues and changes that reveal pathophysiology in disease. These methods present remarkable opportunities to understand the cellular and molecular underpinnings of Alzheimer’s disease pathology, and how those changes impact the structural and functional organization of tissue and circuit microarchitecture that ultimately leads to cognitive decline. The Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD1.0) established best practices for postmortem tissue preparation that preserves tissue integrity and RNA quality and overcame technical hurdles such as tissue autofluorescence to establish an effective strategy for applying spatial transcriptomics methods (specifically MERFISH) to tissues with varying Alzheimer’s disease (AD) neuropathological burden. These methods complement single nucleus RNA-seq analysis of AD tissues from Project 2 that identified cell type-specific vulnerabilities and molecular pathways dysregulated in AD, using gene panels derived from transcriptomic reference classifications. These data validate disease-associated changes in cell type proportions and provide essential confirmation of AD- relevant cellular changes, while adding novel information about the relative topography and spatial relationships among disease affected cell types. SEA-AD2.0 will expand on spatial analyses to characterize cellular and molecular changes with AD and cormorbid dementias (AD/ADRDs). MERFISH will be used to validate and expand on findings from single nucleus Multiome analysis on AD Spectrum cases spanning the range of AD (beta amyloid and ptau) pathology across a range of brain regions including those affected early in disease. We will also analyze a larger and highly diverse AD and AD/ADRD Spectrum cohort including polypathologies, racial/ethnic diversity, topological and cognitive subtypes, and resistance and resilience phenotypes. MERFISH will validate changes in cell proportions from Multiome analyses across various affected regions in the brain, and across different axes of donor diversity that show robust disease phenotypes. In targeted sets of donors, we will analyze dysregulated genes with enhanced computational analyses and spatial statistics describing affected cell types and their spatial relationships. Finally, we will implement and benchmark a new set of commercially available technologies to characterize cell type-specific vulnerabilities using combined proteomic and transcriptomic methods. We will assess the relationship between neuropathologic proteins and affected cell types, as well as the relationship of cell types and disease severity to important structural and functional changes such as myelination, inflammation and synaptic dysfunction or loss. Together, these efforts will produce by far the most detailed understanding of cell type changes in AD, variation across AD/ADRD diversity, and their relationship to the biology underlying cognitive changes in AD and AD/ADRD. Data produced in this project will be integrated with Projects 1 and 2 and made publicly accessible through the Data Core.