Single-nucleus multiomic profiling uncovers epigenetic dysregulation driving hippocampal vulnerability in Alzheimer’s disease

AI Summary

Integrated single-nucleus RNA and ATAC profiling of human hippocampus identifies over 1,000 disease-associated cis regulatory interactions linking chromatin accessibility to transcriptional remodelling.
Excitatory cornu ammonis neurons show disproportionate regulatory disruption, increased chromatin accessibility and activation of apoptosis gene programmes; dentate gyrus neurons remain comparatively resistant.
SPI1 KLF4 microglial and STAT3 astrocytic modules drive inflammatory and metabolic transitions; numerous AD regulatory elements are human specific and enriched at BIN1 and APOE.

TL;DR (AI Generated)

In glial cells, regulatory network inference revealed activation of transcription factor modules centered on SPI1/KLF4 in microglia and STAT3 in astrocytes, defining epigenetic programs that are highly associated with inflammatory and metabolic state transitions.

Furthermore, cross-species integration demonstrated that a substantial fraction of AD-associated regulatory elements are human-specific, with AD-risk variants enriched in microglial cis-regulatory elements at loci including BIN1 and APOE.

Together, these results provide a mechanistic framework linking chromatin remodeling to cell-type-specific dysfunction and reveal human-specific regulatory architecture as a crucial factor to AD vulnerability and translational limitation.

Basic summary

Sci Adv. 2026 Nov 13;12(46):eaee4760. doi: 10.1126/sciadv.aee4760. Epub 2026 Nov 13.

ABSTRACT

Alzheimer’s disease (AD) exhibits region- and cell-type-specific vulnerability, yet the underlying regulatory mechanisms remain poorly defined. We performed integrated single-nucleus RNA-seq and ATAC-seq of human hippocampus to resolve gene regulatory architecture in AD. By linking chromatin accessibility to transcription, we identified more than 1000 disease-associated cis-regulatory interactions, highlighting coordinated epigenomic-transcriptomic remodeling. Excitatory cornu ammonis (EX.CA) neurons exhibited disproportionate regulatory disruption, characterized by increased chromatin accessibility coupled to activation of apoptosis-related gene programs, whereas dentate gyrus (EX.DG) neurons remained comparatively resistant. In glial cells, regulatory network inference revealed activation of transcription factor modules centered on SPI1/KLF4 in microglia and STAT3 in astrocytes, defining epigenetic programs that are highly associated with inflammatory and metabolic state transitions. Comparative evaluation with the prefrontal cortex uncovered conserved inflammatory activation alongside region-specific immune regulatory divergence, indicating spatially distinct microglial responses. Furthermore, cross-species integration demonstrated that a substantial fraction of AD-associated regulatory elements are human-specific, with AD-risk variants enriched in microglial cis-regulatory elements at loci including BIN1 and APOE. Together, these results provide a mechanistic framework linking chromatin remodeling to cell-type-specific dysfunction and reveal human-specific regulatory architecture as a crucial factor to AD vulnerability and translational limitation.

PMID:43024710 | DOI:10.1126/sciadv.aee4760

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