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. Overall design: Nuclei were isolated from postmortem prefrontal cortex (PFC,n=9), entorhinal cortex (EC, n=6), and hippocampus (HIP, n=5) of sprodic early-onset Alzheimer's Disease patient (n=4) and matched controls (n=5). The isolated nuclei were then subjected to single-nuclei multiome sequcing. ll tissues were de-identified under The Health Insurance Portability and Accountability Act of 1996 (HIPAA) privacy rules. The tissue donation consent was obtained from all participants by UTHealth.