Researchers from Carnegie Mellon University’s School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington have discovered a previously underexplored feature of Alzheimer’s disease that may help scientists identify new treatment avenues.
The study, published in Sciencediscovered that the three-dimensional organization of the genome in certain brain cells differs from that of people with Alzheimer’s disease. Scientists from SCS’s Ray and Stephanie Lane Department of Computational Biology, Pitt’s Department of Neurobiology, and collaborating institutions connected these changes in genome folding to changes in gene activity and brain tissue organization.
To build this detailed image, 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 layer by layer,” said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology, who led and supervised the study. “The three-dimensional structure of the genome is a critical regulatory layer that helps connect DNA sequence to gene activity. By integrating genome folding, cellular state, and tissue context, we can go beyond cataloging disease-associated changes and understand how they fit together and what mechanisms to test next.”
DNA is not found 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. Therefore, changes in that physical organization can influence the functioning of cells.
The researchers examined postmortem samples of the prefrontal cortex, an area at the front of the brain. The tissue came from people with and without Alzheimer’s who had participated in a long-term dementia study and subsequently donated their brains for research.
The team used GAGE-seq, a technique that can measure both gene expression and three-dimensional contacts of the genome 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 data sets together, the researchers were able to connect the physical organization of the genome to gene regulation while also looking at where Alzheimer’s-related molecular and cellular changes appeared within the surrounding tissue.
A new layer of Alzheimer’s biology
“Our study represents an important advance in understanding what goes wrong in Alzheimer’s disease,” said Hansruedi Mathys, assistant professor of neurobiology in Pitt’s Department of Neurobiology, who led 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.”
Beta amyloid 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 composed of DNA and associated proteins that package the genome within cells, should also be considered part of the molecular landscape of the disease.
AI connects genome folding with genetic activity
Another important part of the research was Hicformer, an artificial intelligence model developed to investigate how genome structure can influence cell behavior. The model combines DNA sequence information with broad genome folding patterns and detailed maps showing where different sections of DNA physically come into contact with each other.
Using this data, Hicformer predicts gene activity in different cell types. Xinyue Lu, a PhD student in Computational Biology who co-led the research, described the system as a computational testbed that can be used to explore how changes in genome folding could alter gene activity.
“Measuring gene activity and genome folding in the same cell allows us to directly connect chromosome structure to disease-related genetic programs,” said Yang Zhang, project scientist in the Department of Computational Biology, who co-led the research. “Across several brain cell types, 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 investigations.”
DNA organization becomes less distinctive
The researchers identified several consistent differences in the genome architecture of cells from people with Alzheimer’s disease.
Large sections of the genome are typically organized into relatively distinct active and inactive regions known as compartments. In Alzheimer’s cells, those boundaries seemed less defined. The researchers describe this pattern as “increased mixing of compartments.”
Several types of brain cells also showed fewer interactions between nearby sections of the genome and more contacts between regions located further away. Cells with greater compartment mixing tended to have lower overall levels of gene activity.
The team also observed weaker interactions between the genes and nearby regulatory elements that normally help control whether those genes are turned 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 responses to stress. 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 in intact brain tissue, they found that the genome reorganization was related not only to altered genetic activity but also to differences in how brain cells were organized within the tissue.
The results establish that the three-dimensional organization of the genome is another important layer of the biology of Alzheimer’s disease. They also provide researchers with a framework to test what changes in genome architecture might directly contribute to 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 funded 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, graduate researchers 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 Center for Alzheimer’s Disease.