Single-cell epigenomics and transcriptomics reveals altered circuitry in Alzheimer's disease across multiple brain regions
Alzheimer's disease (AD) is a widespread progressive neurodegenerative disorder marked by cognitive decline and memory loss, yet its epigenetic underpinnings remain largely elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic data to reveal alterations during AD progression across 3.5 million cells, 384 post-mortem brain samples, 6 brain regions, and 111 AD and age-matched control individuals. We characterize more than 1 million candidate cis-regulatory elements (cCREs) grouped into 123 coordinated regulatory modules. We delineate AD-associated epigenomic changes in large-scale epigenomic compartments and single-cell epigenomic information dynamics, highlighting global epigenomic relaxation and loss of epigenomic identity, revealing brain-region-specific epigenomic erosion properties and vulnerable cell types. We find that epigenomic information changes are highly associated with cell-type compositional dynamics and glial cell state transitions in AD, particularly in glial cell activation and exhaustion. We systematically characterize transcriptomic and epigenomic alterations linked to epigenomic stability, finding that changes are highly correlated with molecular alterations related to AD pathologies, cognitive functions, and resilience. Overall, our findings offer new insights into the epigenomic dysregulation in AD progression and cognitive resilience, and a valuable single-cell multiomic atlas to advance our understanding of AD.
