Researchers at Carnegie Mellon University, the University of Pittsburgh, and the University of Washington have identified disruptions in the 3D organization of DNA in brain cells affected by Alzheimer’s disease. The findings, published in *Science*, reveal a previously unexplored layer of the disease that could lead to new treatment avenues.
The study connected changes in genome folding with shifts in gene activity and the organization of brain tissue. Scientists used a combination of single-cell technology, spatial mapping of brain tissue, and a deep learning model to build a detailed picture of these changes. The research focused on postmortem samples from the prefrontal cortex of individuals with and without Alzheimer’s disease who participated in a long-term dementia study.
“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 University, who led and supervised the study. “The genome's 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity. By integrating genome folding, cell state, and tissue context, we can move beyond cataloging disease-associated changes toward understanding how they fit together and which mechanisms to test next.”
The team utilized GAGE-seq, a technique measuring both gene expression and three-dimensional genome contacts within individual cells, alongside spatial transcriptomic maps to preserve information about gene activity within brain tissue. This allowed researchers to connect the physical organization of the genome with gene regulation and pinpoint Alzheimer’s-related molecular and cellular changes within the surrounding tissue. The research suggests that changes in the way DNA folds can influence cell function and contribute to the development of Alzheimer’s disease.
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