Faculty, Staff and Student Publications
Language
English
Publication Date
12-19-2025
Journal
Science Advances
DOI
10.1126/sciadv.adw4917
PMID
41406216
PMCID
PMC12710691
PubMedCentral® Posted Date
12-17-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Sporadic early-onset Alzheimer’s disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer’s disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type–specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 33 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and found that, in addition, sEOAD cCREs are enriched for neuropsychiatric disorder risk variants. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.
Keywords
Humans, Alzheimer Disease, Brain, Male, Female, Transcriptome, Gene Expression Regulation, Transcription Factors, Aged, Hippocampus, Entorhinal Cortex, Multiomics
Published Open-Access
yes
Recommended Citation
Liu, Andi; Citu, Citu; Enduru, Nitesh; et al., "Single-Nucleus Multiomics Reveals the Disrupted Regulatory Programs in Three Brain Regions of Sporadic Early-Onset Alzheimer’s Disease" (2025). Faculty, Staff and Student Publications. 805.
https://digitalcommons.library.tmc.edu/uthshis_docs/805