Alzheimer’s Disrupts the 3D Folding of DNA in Brain Cells, New Study Finds

A study published in Science in July 2025 (DOI: 10.1126/science.adz1652) from researchers at Carnegie Mellon University, the University of Pittsburgh, and the University of Washington has revealed that Alzheimer’s disease fundamentally disrupts the three-dimensional folding of DNA inside individual brain cells. This disruption, which they named “increased compartment mingling,” is linked to lower gene activity and may point toward new therapeutic targets .

What the Study Found: 3D Genome Folding Goes Awry

The human genome is not a random tangle of DNA. Inside the cell nucleus, chromosomes fold into distinct three-dimensional neighborhoods. Large stretches of active DNA are normally kept in separate “compartments” from inactive DNA, a structure that ensures the right genes are turned on in the right cells.

By mapping the 3D folding of DNA in single brain cells from people with Alzheimer’s disease, the researchers discovered that this organization breaks down. Active and inactive genomic compartments become less distinct and more intermixed compared to cells from healthy individuals .

Key findings:

• Fewer short-range DNA contacts, more long-range contacts across several types of brain cells.
• Greater mingling was associated with reduced gene expression, particularly in neuronal and synaptic gene programs.
• The reorganization was linked to weakened contacts between genes and their regulatory elements .

The Pattern: ‘Increased Compartment Mingling’

The team coined the term “increased compartment mingling” to describe the observed disruption. This pattern — characterized by the mixing of active and inactive genomic neighborhoods — was present in multiple cell types in Alzheimer’s brains, and the degree of mingling correlated with the severity of gene expression loss .