Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease

Alzheimer's disease (AD) disrupts brain function through cell type-specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type-specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type-specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration.