The way DNA is folded inside brain cells appears to differ in Alzheimer's disease, according to a study published in Science by researchers at Carnegie Mellon University's School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington. Working with tissue from the prefrontal cortex, the team found that 3D genome architecture is arranged differently in certain brain cells from people with the disease, and connected that folding to patterns of gene activity and to how brain tissue itself is organized.
The samples came from postmortem prefrontal cortex tissue donated by participants in a long-term dementia study, both with and without Alzheimer's. To link the layers together, the researchers used GAGE-seq, a technique that measures gene expression and 3D genome contacts within the same individual cell, and combined those readings with spatial transcriptomic maps of intact tissue. A new deep learning model helped tie the single-cell and tissue-scale data into one picture.
That combination matters because it changes the kind of question researchers can ask. Rather than compiling separate lists of genes, cell types or molecular changes associated with Alzheimer's, the approach places those changes in relation to one another and to their physical location in the brain. Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology, who led the study, described the genome's 3D structure as a fundamental regulatory layer connecting DNA sequence to gene activity, and argued that Alzheimer's cannot be understood one layer at a time.
The practical payoff is direction. By showing which folding changes line up with altered gene regulation in which cell states and tissue contexts, the work narrows the field of mechanisms worth testing experimentally - a step the authors frame as moving from cataloging disease-associated changes toward figuring out how they fit together. This is foundational biology from human brain tissue, not a treatment, but it opens a layer of Alzheimer's biology that had gone largely unexplored.