Decoding Alzheimer's Disease: Single-Cell Sequencing Uncovers Brain Cell Heterogeneity and Pathogenesis

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by progressive cognitive decline and diverse neuropathological features. Recent advances in single-cell sequencing technologies have provided unprecedented insights into the cellular and molecular heterogeneity of the AD brain. This review systematically summarizes the applications of single-cell transcriptomic and epigenomic approaches in AD research, with a focus on the characterization of cell type- and subtype-specific transcriptomic alterations. This review highlights key discoveries related to selectively vulnerable neuronal and glial subpopulations, as well as transcriptional dysregulation associated with genetic risk loci such as APOE and TREM2. This review also discusses how the integration of single-cell RNA sequencing (scRNA-seq), assays for transposase-accessible chromatin using sequencing (ATAC-seq), and spatial transcriptomics elucidates disease trajectories and cellular communication networks across pathological stages. These insights not only enhance the understanding of the pathogenesis of AD but also pave the way for precision medicine through the identification of novel therapeutic targets and biomarkers.

Keywords: ATAC-seq; Alzheimer’s disease; Cell heterogeneity; Gene regulation; Neuropathology; Single-cell sequencing.