Scientists Find a Hidden Layer of Alzheimer's in How the Genome Folds

Researchers at Carnegie Mellon University, the University of Pittsburgh and the University of Washington have found that the three-dimensional folding of the genome — the physical shape DNA takes inside a cell — differs in certain brain cells of people with Alzheimer's disease. The study, published in the journal Science, links these changes in genome folding to shifts in gene activity and to the organisation of brain tissue itself.

"Alzheimer's disease cannot be understood one layer at a time," said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology at Carnegie Mellon, who led the study. "The genome's 3D structure is a fundamental regulatory layer that helps connect DNA sequence to gene activity." 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 for research.

The researchers combined a technique called GAGE-seq, which measures both gene activity and 3D genome contacts within the same individual cell, with spatial maps that preserve information about where in the tissue that activity occurs. They also built an AI model called Hicformer to help predict how genome folding influences gene activity across different brain cell types.

"Our results establish higher-order chromatin alterations as a component of the molecular pathology associated with the disease, which currently affects seven million Americans, a number that continues to grow," said Hansruedi Mathys, an assistant professor of neurobiology at Pitt who directed that part of the study. In Alzheimer's cells, regions of the genome normally organised into distinct active and inactive "compartments" showed less sharply defined boundaries — a pattern the researchers call "increased compartment mingling" — and cells with more of this mingling tended to have lower overall gene activity.

The structural changes were linked to reduced activity in genes involved in neurons and synapses, along with shifts in metabolism and cellular stress responses, as well as ageing-related changes in microglia, the immune cells that help maintain brain health. Amyloid-beta plaques and tau tangles remain the best-known biological hallmarks of Alzheimer's, but the researchers say genome folding should now be considered part of the disease's molecular picture too.