Language

English

Publication Date

9-28-2023

Journal

Cell

DOI

10.1016/j.cell.2023.08.040

PMID

37774680

PMCID

PMC10782612

PubMedCentral® Posted Date

9-28-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.

Keywords

Humans, Alzheimer Disease, Brain, Epigenome, Epigenomics, Gene Expression Regulation, Genome-Wide Association Study

Published Open-Access

yes

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