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.

Fig. 1

The cumulative dysfunction of multiple cell types in Alzheimer’s disease drives the progression of neurodegeneration. Brain tissue was processed into a single-cell suspension and subjected to scRNA-seq analysis to explore cell heterogeneity. In AD, excitatory neurons exhibit hyperactivity before their loss while selectively vulnerable inhibitory neurons are depleted. Microglia in AD exist in various states, including resting microglia, MAEAD, and MALAD. TREM2 plays a key role by promoting the transcriptional activation of resting microglia, enabling them to engage in Aβ phagocytosis. However, microglial subpopulations involved in synaptic pruning and clearance are lost under AD-related stress. Moreover, astrocytes associated with AD downregulate neurotransmitter metabolism-related genes such as SLC1 A2 and GLUL, leading to dysregulation of neurotransmitter cycling. This dysfunction results in excitotoxicity, which contributes to neuronal death. Similarly, oligodendrocytes in AD downregulate myelination-related genes, including MAG and MOBP. This reduction in gene expression decreases the population of mature myelinating oligodendrocytes, further promoting neuronal degeneration. In addition, vascular endothelial cells in AD upregulate angiogenesis-related genes like CLDN5, ERG, and VWF, which induce inflammation and cause immune dysregulation. At the same time, the downregulation of ABCB1 and ATP10 A in endothelial cells compromises the integrity of the BBB, leading to its disruption. This cumulative impact of dysfunction of various cell types in AD contributes to the overall progression of the disease. BBB, blood–brain barrier; MAEAD, microglia associated with early AD; MALAD, microglia associated with late AD