2025-08-21
Single-cell epigenomic rewiring in alzheimer’s disease progression and cognitive resilience
Neurology
By Lila Rouland | Published on août 21, 2025 | 2 min read
#Alzheimer #CognitiveResilience
Alzheimer’s disease (AD) remains the leading cause of dementia, characterized by progressive memory loss and neuronal degeneration. While the accumulation of amyloid plaques and tau tangles is well established, the epigenetic mechanisms underlying neuronal vulnerability and resilience are still poorly understood.
In this landmark study, researchers created a single-cell multi-omic atlas of 3.5 million cells from 384 post-mortem brain samples, covering six brain regions from 111 individuals with and without AD.
The work integrates snATAC-seq, RNA-seq, and multiome data, enabling the mapping of over one million cis-regulatory elements (cCREs) and 123 regulatory modules across 67 cellular subtypes. This unprecedented dataset reveals how epigenomic instability, nuclear compartment disruption, and transcriptional dysregulation fuel AD progression, while preserved stability supports cognitive resilience.
Mapping the brain epigenome: a region-by-region exploration
The study focused on six key regions: entorhinal cortex (EC), hippocampus (HC), prefrontal cortex (PFC), middle temporal cortex (MTC), angular gyrus (AG), and thalamus (TH). These areas represent both early- and late-stage vulnerable regions in AD progression.
Cells were hierarchically classified into seven main classes (excitatory neurons, inhibitory neurons, oligodendrocytes, astrocytes, microglia, oligodendrocyte progenitor cells [OPCs], and vascular cells), and further subdivided into 67 subtypes.
Analysis of
chromatin accessibility, transcription factor (TF) motifs, and cCRE modules
highlighted region- and cell type–specific regulatory networks.
Crucially, genome-wide nuclear compartmentalization was investigated. In a healthy brain, chromatin alternates between active compartments (gene-rich, accessible) and repressive compartments (silent, lamina-associated). In AD, a widespread rewiring occurs: repressive chromatin becomes active and vice versa—particularly in the EC and HC.
Crucially, genome-wide nuclear compartmentalization was investigated. In a healthy brain, chromatin alternates between active compartments (gene-rich, accessible) and repressive compartments (silent, lamina-associated). In AD, a widespread rewiring occurs: repressive chromatin becomes active and vice versa—particularly in the EC and HC.
Epigenomic
erosion: correlation with cognitive decline
1. Global epigenomic relaxation
Advanced AD samples show widespread activation of normally repressive chromatin (e.g., chr18) and repression of normally active chromosomes (e.g., chr19). This indicates a loss of nuclear compartment fidelity and transcriptional precision.
2. Loss of epigenomic information
Single-cell analyses reveal a general reduction in epigenomic information across all cell classes, particularly in glial cells (oligodendrocytes, OPCs, microglia) and vulnerable excitatory neurons in the EC and HC. Superficial-layer excitatory neurons in the neocortex and SST inhibitory neurons also show marked erosion.
3. Glial activation followed by exhaustion
Initially, glial cells gain epigenomic identity during activation. However, under prolonged stress, they lose stability and enter exhausted states. Activated microglia and astrocytes show a sharp drop in epigenomic information—especially in APOE4 carriers.
4. Cognitive resilience and epigenomic preservation
Unlike pathological profiles, cognitively resilient individuals (who maintain function despite pathology) display higher epigenomic information across the brain. Vulnerable neurons retain stability, and activated glia avoid exhaustion. This suggests that preservation of epigenomic integrity underlies resilience.
Regulatory networks: from stability to dysfunction
Stable cells protect chromatin and the nucleus (ASTN2, RORA, VCAN), while eroded cells activate stress and inflammation pathways (APOE, CST3, VIM). Polycomb complexes act as epigenomic guardians.
In practice: strengthening nuclear structure, maintaining heterochromatin, or targeting chromatin regulators could protect neurons and preserve cognition. This represents a promising avenue for personalized epigenetic interventions against Alzheimer’s disease.
Read next: Mood, memory, inflammation—could it all happen on the plate?
About the Author – Lila Rouland
Doctor of Oncology, specialized in Biotechnology and Management
With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.
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