Overview

• The multimodal atlas profiles about 3.5 million cells from 384 post‑mortem samples across 111 donors, integrating single-cell RNA-seq with ATAC-seq.
• Analyses identify two pervasive trends in diseased tissue: loss of nuclear compartmentalization and erosion of cell-specific epigenomic information.
• Epigenomic deterioration is most pronounced in early-affected regions such as the entorhinal cortex and hippocampus and in vulnerable cell types including microglia, oligodendrocytes, and select excitatory neurons.
• Cells with greater erosion show abnormal opening of Polycomb-repressed regions and increased expression of inflammation and oxidative stress genes, correlating with lower cognitive scores.
• The dataset annotates more than one million regulatory elements and reports APOE4-linked microglial dynamics that rise early then decline with progression, offering a resource for future mechanistic and therapeutic studies.