ALZHEIMERS RESEARCH PROJECT: Dissecting Common and Distinct Disease Signatures Across AD/ADRD Postmortem Brain Samples Through Single-cell and Spatial Profiling

National Institute On Aging

Investigators

Abstract

This project aims to explore the molecular underpinnings of Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE), with a specific focus on distinguishing cases with and without TDP-43 proteinopathies. By doing so, we seek to better understand how TDP-43 pathology influences the disease mechanisms and whether there are shared molecular features that cut across these neurodegenerative disorders. We will create an integrative atlas of brain tissue samples from control, AD, and FTD cases, leveraging both published and unpublished single-nucleus RNA sequencing (snRNA-seq) data. This will allow for a detailed comparison of the transcriptomic profiles between diseases and within different regions of the brain. In addition, we will conduct spatial transcriptomics using advanced technologies like Visium and Xenium on tissue samples obtained from multiple brain banks. These techniques will enable us to map the spatial distribution of TDP-43 aggregates and the surrounding transcriptomic landscape to gain insight into how nearby cells are impacted by these pathological structures and vice-versa. Through these integrated analyses, the project aims to uncover key patterns of cellular vulnerability and resilience that are unique to each disease. Moreover, by focusing on cases with and without TDP-43 pathology, we will explore whether there are shared molecular pathways across AD, FTD, and LATE that could lead to common therapeutic targets. Ultimately, the study will contribute to a deeper understanding of disease mechanisms in AD/ADRD and inform the development of targeted treatments for these devastating conditions.