Researchers at Carnegie Mellon University’s School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington have uncovered a previously underexplored feature of Alzheimer’s disease that may help scientists identify new avenues for treatment.
The study, published in Science, found that the three-dimensional organization of the genome differs in certain brain cells from people with Alzheimer’s disease. Scientists from SCS’s Ray and Stephanie Lane Computational Biology Department, Pitt’s Department of Neurobiology, and collaborating institutions connected these changes in genome folding with shifts in gene activity and the organization of brain tissue.
To build this detailed picture, the team combined single-cell technology, spatial mapping of brain tissue, and a newly developed deep learning model.
Looking Beyond Amyloid and Tau
“Alzheimer’s disease cannot be understood one layer at a time,” said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology 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.”
DNA does not sit inside a cell as a simple straight strand. Instead, it folds into a complex three-dimensional structure that helps determine which genes are accessible and active. Changes in that physical organization can therefore influence how cells function.
The researchers examined postmortem samples from the prefrontal cortex, an area at the front of the brain. The tissue came from people with and without Alzheimer’s disease who had taken part in a long-term dementia study and later donated their brains for research.
The team used GAGE-seq, a technique that can measure both gene expression and three-dimensional genome contacts within the same individual cell. Those measurements were then combined with spatial transcriptomic maps, which preserve information about where gene activity occurs within intact brain tissue.
By bringing these datasets together, the researchers were able to connect the physical organization of the genome with gene regulation while also seeing where Alzheimer’s related molecular and cellular changes appeared within the surrounding tissue.
A New Layer of Alzheimer’s Biology
“Our study represents a major advance in understanding what goes wrong in Alzheimer’s disease,” said Hansruedi Mathys, assistant professor of neurobiology at Pitt’s Department of Neurobiology, who directed the Pitt arm of the study. “We know the classic hallmarks of Alzheimer’s disease – accumulation of amyloid-beta plaques and tau tangles – but 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.”
Amyloid beta plaques and tau tangles are among the best known biological features of Alzheimer’s disease. The new findings suggest that changes in chromatin, the material made of DNA and associated proteins that packages the genome inside cells, should also be considered part of the disease’s molecular landscape.
AI Connects Genome Folding to Gene Activity
Another important part of the research was Hicformer, an artificial intelligence model developed to investigate how genome structure may influence cellular behavior. The model combines DNA sequence information with broad patterns of genome folding and detailed maps showing where different sections of DNA physically contact one another.
Using these inputs, Hicformer predicts gene activity across different types of cells. Xinyue Lu, a doctoral student in Computational Biology who co-led the research, described the system as a computational test bed that can be used to explore how changes in genome folding might alter gene activity.
“Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure with disease-related gene programs,” said Yang Zhang, a project scientist in the Computational Biology Department who co-led the research. “Across several kinds of brain cells, this paired view revealed a consistent signature of 3D genome reorganization in Alzheimer’s disease and helped us prioritize regulatory regions for future mechanistic and therapeutic investigation.”
DNA Organization Becomes Less Distinct
The researchers identified several consistent differences in the genome architecture of cells from people with Alzheimer’s disease.
Large sections of the genome are normally organized into relatively distinct active and inactive regions known as compartments. In Alzheimer’s cells, those boundaries appeared less sharply defined. The researchers describe this pattern as “increased compartment mingling.”
Several kinds of brain cells also showed fewer interactions between nearby sections of the genome and more contacts between regions located farther apart. Cells with greater compartment mingling tended to have lower overall levels of gene activity.
The team also observed weaker interactions between genes and nearby regulatory elements that normally help control whether those genes are switched on or off. At the same time, some contacts across intermediate distances became stronger.
These structural differences were associated with reduced activity in programs involved in neurons and synapses, along with changes in metabolism and cellular stress responses. The researchers also found links to senescence-related programs in microglia, immune cells in the brain that play important roles in maintaining brain health and responding to damage.
Potential Clues for Future Alzheimer’s Treatments
When the researchers mapped these molecular changes across intact brain tissue, they found that the reorganization of the genome was connected not only to altered gene activity but also to differences in how brain cells were arranged within the tissue.
The results establish three-dimensional genome organization as another important layer of Alzheimer’s disease biology. They also provide researchers with a framework for testing which changes in genome architecture might directly contribute to the disease.
Future studies can now investigate whether particular structural changes help drive Alzheimer’s progression and whether any of the affected regulatory regions could eventually become targets for new therapies.
The research was supported by grants from the National Institutes of Health. Other CMU authors included doctoral students Shahul Alam and Shike Wang and postdoctoral research associate Junjie Tang. Other Pitt authors include doctoral students Alexander K. Kunisky and Jude Baroudi, post-baccalaureate research fellows Sahar and Sahel Ghorbanikalateh, and visiting scholar Shihan Wang. The team included researchers from the Broad Institute of MIT and Harvard; the University of California, Los Angeles; the University of Washington; and the Rush Alzheimer’s Disease Center.
