Erosion of Epigenetic Control in the Alzheimer’s Brain – Fight Aging!

The low cost of omics tools combined with the ability to distinguish the behavior of individual cells from a tissue sample allows for the creation of ever larger databases of epigenetic and transcriptional profiles of the aging brain. Creating these databases is one thing, and the results are of great interest, but comparatively little progress has been made on the leap from a mass of data describing how an aged brain differs from a young brain to an understanding of cause and effect in those observed changes. That understanding is necessary in order to build effective therapies, but establishing it is also the hard part of the problem.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals.

We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience.

This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.

Link: https://doi.org/10.1016/j.cell.2025.06.031