Single-nucleus multiomics reveals the regulatory programs in three brain regions of sporadic early-onset Alzheimer's Disease

Sporadic early-onset Alzheimer’s Disease (sEOAD) represents a significant but less-studied subtype of Alzheimer’s Disease. In this study, we generated a single-nucleus multiome atlas from over 70,000 nuclei derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of four sEOAD patients and five control donors. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across these brain regions. We identified and prioritized seven conservative transcription factors in glial cells and neurons in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in the regulation of sEOAD-associated genes. Moreover, we investigated altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. Finally, we reported an enrichment of late-onset Alzheimer’s Disease risk loci within microglial cCREs linked to sEOAD-associated genes. This atlas enhances our understanding of the transcriptional and chromatin dynamics in sEOAD and provides a foundational resource for further pathological investigations.