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A new multimodal atlas constructed by researchers at the Massachusetts Institute of Technology reveals that the progression of Alzheimer’s disease involves widespread changes in the regulation of gene expression in brain cells. The findings, published in Cell, offer a high-resolution account of how disruptions in epigenomic integrity correlate with both the severity of brain pathology and the extent of cognitive decline.
The study analyzed 384 post-mortem brain samples from 111 individuals, spanning 6 brain regions. In total, more than 3.5 million cells were profiled using single-cell RNA sequencing and ATAC-seq. This allowed the team to map both the transcriptome and the epigenome – the machinery responsible for which genes are activated or repressed in different cell types.
Epigenome
The epigenome consists of chemical modifications to DNA and associated proteins that regulate gene activity without altering the DNA sequence.
Transcriptome
The transcriptome is the complete set of RNA molecules produced by cells, reflecting which genes are being expressed at a given time.
Two central patterns of epigenomic deterioration
Comparative analysis of brains with and without Alzheimer’s pathology revealed two main trends in epigenomic disruption. First, cells in vulnerable brain regions lost the compartmental organization of their nuclear architecture, leading to inappropriate opening and closing of DNA regions involved in gene expression. Second, these same cells exhibited a loss of epigenomic information, indicating they could no longer sustain the regulatory patterns that define their identity and function.
“To understand the circuitry, the logic responsible for gene expression changes in Alzheimer’s disease, we needed to understand the regulation and upstream control of all the changes that are happening, and that’s where the epigenome comes in.”
Dr. Manolis Kellis.
The researchers created an epigenomic information score to quantify these changes at the single-cell level. Cells from the hippocampus and entorhinal cortex – regions typically affected early in Alzheimer’s – showed marked decreases in these scores as disease advanced. The most vulnerable cell types included microglia, oligodendrocytes and certain excitatory neurons.
Link between chromatin state and cognitive decline
The breakdown of epigenomic regulation appeared to coincide with the activation of disease-related gene networks and a decline in cognitive ability. Where cells preserved compartmental structure and regulatory control, cognition tended to be maintained. Conversely, cells with more disordered chromatin states were associated with increased expression of genes involved in inflammation and oxidative stress.
The researchers also identified over 1 million gene-regulatory control regions that different cell types use to sustain their specific function. Comparing patterns across the disease continuum, they observed that regions typically repressed in healthy cells became accessible in advanced disease, allowing harmful gene expression programs to emerge.
Insights into Alzheimer’s risk genes
The study also explored how genetic risk factors for Alzheimer’s intersect with epigenomic changes. For instance, in individuals carrying two copies of the APOE4 variant, microglia initially increased their regulatory complexity – suggesting an early compensatory response – but later showed steep declines as the disease progressed. This trajectory may help explain the high risk associated with this genotype.
Neurons expressing the RELN gene, previously identified as susceptible in Alzheimer’s, also showed early and severe epigenomic information loss. However, in cognitively resilient individuals, these neurons retained their regulatory patterns, highlighting a potential axis of disease resistance.
Chromatin guardians and nuclear disorder
Cells undergoing epigenomic erosion showed increased accessibility in genomic regions that are normally repressed by proteins such as Polycomb group regulators. These findings suggest that the loss of “chromatin guardians” may be a key feature of disease vulnerability. In contrast, cells from resilient individuals continued to express genes associated with synaptic function and neural connectivity.
Chromatin
Chromatin is the complex of DNA and proteins found in the cell nucleus.
Polycomb group proteins
These proteins are part of a family of gene repressors that maintain cell identity by preventing inappropriate gene expression.
By assembling a comprehensive gene-regulatory map of Alzheimer’s disease across multiple brain regions and stages, the study offers a reference point for future research into the molecular underpinnings of neurodegeneration. While the work does not identify direct therapeutic targets, it emphasizes the role of epigenomic control in maintaining neuronal identity and function.
“The key to developing new and more effective treatments for Alzheimer’s disease depends on deepening our understanding of the mechanisms that contribute to the breakdowns of cellular and network function in the brain.”
Dr. Li-Huei Tsai.
Reference: Liu Z, Zhang S, James BT, et al. Single-cell multiregion epigenomic rewiring in Alzheimer’s disease progression and cognitive resilience. Cell. 2025:S0092867425007330. doi: 10.1016/j.cell.2025.06.031
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