Alzheimer's disease doesn't just change which genes are active in brain cells — it appears to change how the DNA itself is folded, according to a new single-cell study published in Science.
The three-dimensional way DNA folds inside a cell's nucleus helps control which genes switch on and off. Researchers found that in Alzheimer's, this folding is reorganized: short-range interactions within the genome decrease while longer-range ones increase, disrupting normal gene regulation.
How they found it
The team used a technique called GAGE-seq to measure genome folding and gene activity in the same individual cells, combined with spatial mapping and an AI model named Hicformer. They applied it to postmortem prefrontal cortex tissue from people with and without Alzheimer's. The work came from Carnegie Mellon University, the University of Pittsburgh, and the University of Washington.
“The genome's 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity,” said Carnegie Mellon's Jian Ma. Colleague Yang Zhang added that measuring both in the same cell “allows us to directly connect chromosome structure” to disease.
Why it matters
The findings point to genome folding as a “previously underappreciated regulatory layer” in Alzheimer's. This is early, mechanistic science — not a treatment — but understanding how the disease disrupts the genome's architecture could reveal new targets for drugs down the line.