Scientists have discovered that the three-dimensional shape of DNA inside brain cells is disrupted in Alzheimer's disease, uncovering a previously hidden layer of the illness that could point researchers toward new treatments. Researchers at Carnegie Mellon University, the University of Pittsburgh and the University of Washington found that the way the genome folds differs in certain brain cells from people with Alzheimer's, changing which genes are switched on and off. The study, published in Science, links these structural changes to shifts in gene activity and to the way brain tissue itself is organized.
Lucy Hooper, a medical doctor and co-founder of Coyne Medical, who was not involved in the study, told Newsweek that research using human brain cells carries particular weight because so much existing knowledge of Alzheimer's has come from animal models. "We know, clearly, that we are very different from a mouse, so having more studies that use human biology is really important," Hooper said. She said the findings add to growing evidence of how complex Alzheimer's biology really is, beyond the amyloid plaques and tau tangles taught in medical school.
"Even the physical way our DNA is folded and organized inside an individual cell may be different in Alzheimer's disease," she said, adding that this falls under epigenetics—the controls that influence how genes are used without changing the underlying DNA sequence. Hooper said epigenetic changes could prove an easier target for future therapies than altering DNA itself, though she cautioned that such treatments remain far from clinical trials. The team examined postmortem prefrontal cortex tissue from people with and without Alzheimer's who had taken part in a long-term dementia study and later donated their brains.
Researchers used a technique called GAGE-seq, which measures both gene activity and three-dimensional genome contacts within the same cell, and combined it with spatial mapping that shows where gene activity occurs within intact brain tissue. They also built a new artificial intelligence model, called Hicformer, to study how genome folding affects cell behavior. DNA normally organizes into distinct active and inactive regions called compartments, but in Alzheimer's cells, the boundaries between those regions were blurred, a pattern the researchers called "increased compartment mingling." Several types of brain cells also showed fewer contacts between nearby DNA sections and more contacts between distant ones.
Cells with more mingling tended to have lower overall gene activity. The team also found weaker links between genes and the regulatory elements that control them, alongside reduced activity in genes tied to neurons, synapses, metabolism and cellular stress. They identified related changes in microglia, the brain's immune cells, connected to cellular aging.
Mapping these changes across brain tissue showed that genome reorganization was tied not just to altered gene activity but to how brain cells were physically arranged. The findings establish genome architecture as an additional layer of Alzheimer's biology, giving scientists a framework to test which structural changes may directly drive the disease. Future studies could determine whether specific alterations contribute to Alzheimer's progression and whether the affected regulatory regions might eventually serve as targets for new therapies.
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