Disentangling the relationship between pathology and cellular vulnerability in Alzheimer's disease

Abstract

Alzheimer's Disease (AD) is the most common cause of dementia affecting approximately 57 million people worldwide. Currently, no effective preventions, treatments, or cures exist. This work ventures to study AD from a new perspective; approaching AD as a cellular disorder that preferentially affects unique subpopulations of cells over time as the disease progresses. The goal of this work is to identify cells vulnerable to dysregulation and cell death at the earliest stages of disease and investigate the role of pathogenic protein accumulation in these processes. The overarching hypothesis of this work was that selectively vulnerable populations of cells preferentially accumulate pathologic peptides and can be identified transcriptomically based on changes in relative abundance and cell state associated with disease progression. This dissertation leverages the massive data collection effort of the multi-center Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) initiative, which includes single-nucleus RNA sequencing (snRNA-seq) and quantitative neuropathology data from a clinical cohort spanning a spectrum of AD pathology. Additionally, high resolution multiomic data, including spatial transcriptomics and pathologic peptide-based single cell RNA sequencing on a subset of SEA-AD donors enables direct assessment of the relationship between protein pathology and cellular vulnerability. Upon completion, the findings generated from this work will serve as a resource for mapping the cellular changes in AD and will identify opportunities for therapeutic intervention at the earliest stages of disease.