Single cell multiomic characterization of the diverse spectrum of Alzheimer's disease across the brain.

Allen Institute, Seattle WA

Investigators

Linked publications & trials

Abstract

ABSTRACT (PROJECT 2) Recent advances in single nucleus genomics have enabled high-resolution characterization of molecular and cellular diversity in the human brain. The Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD1.0) established best tissue preservation practices for high quality genomics assays and developed an effective strategy for applying genomics techniques to tissues from aged individuals with varying Alzheimer’s disease (AD) neuropathological burden, producing a detailed model of disease severity and characterization of vulnerable and disease-associated cell types in multiple brain regions affected by AD. Using integrated quantitative neuropathology and single nucleus genomics SEA-AD1.0 identified disease pseudo-progression trajectories and molecular pathways dysregulated in AD. However, many brain regions impacted by AD remain to be studied, particularly subcortical regions that are among the earliest to show substantial accumulation of AD neuropathologic proteins and widespread neuronal loss with disease progression. Furthermore, most single nucleus genomics studies have been conducted in predominantly non-Hispanic Caucasian populations, despite evidence that disease risk modifying loci can vary among ethnic backgrounds. Likewise, heterogeneity in disease progression resulting from comorbid pathologies and distinct AD subtypes remains to be explored at the cellular level. In SEA-AD2.0, we will apply our genomics-based strategy to interrogate cellular and molecular changes occurring across the brain in donors spanning the spectrum of AD pathology (AD Spectrum), and in a larger, more diverse cohort that encompasses AD and prevalent comorbid dementias (AD and AD/ADRD Spectrum). Multiome (parallel transcriptomic and epigenetic profiling) will be applied in SEA-AD2.0 to target cell type level changes in both gene expression and epigenetic states in relationship to AD and AD/ADRD pathology and disease diagnosis. To characterize brain-wide impacts of AD pathology and determine cellular and molecular changes that occur at the earliest stages of disease prior to the onset of cognitive symptoms, we will sample subcortical regions with early AD pathology, such as cholinergic neurons in the Basal Nucleus of Meynert, and regions of the Default Mode Network that are affected early and whose functions are progressively impacted with increasing AD neuropathological burden in a large cohort of AD Spectrum donors (n=100). To understand variation in cellular and molecular disease signatures across common AD/ADRD co-pathologies, topological and cognitive AD subtypes, sexes, and diverse demographic populations we will analyze a core set of brain regions that span early to late affected areas in an expanded cohort of AD/ADRD Spectrum donors (n=300) with targeted sampling across these axes of diversity to ensure adequate statistical power to test for commonalities and differences between groups. The resulting data will enable identification of shared and brain region-specific vulnerable and disease associated cell types, direct interrogation of dysregulated gene networks in affected cell types, and comparison of cellular and molecular changes in a diverse donor cohort. All data produced in this project will be made publicly accessible.