3D Genome Folding Differs in Alzheimer's Disease

Researchers from Carnegie Mellon University's School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington shed new light on Alzheimer's disease that could point to new directions for treatment.

In a paper published in Science, researchers from SCS’s Ray and Stephanie Lane Computational Biology Department, Pitt’s Department of Neurobiology and collaborating institutions shows that the 3D genome architecture is organized differently in certain brain cells from people with Alzheimer’s disease, uncovering a previously underexplored layer of this disease’s biology. The research team linked genome folding to gene activity and brain tissue organization in Alzheimer’s disease. The research team did this with single-cell technology, spatial mapping of brain tissue, and a new deep learning model.

“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.”

To build this multi-scale view, researchers analyzed postmortem tissue from the prefrontal cortex, a region at the front of the brain, obtained from individuals with and without Alzheimer's disease who had participated in a long-term study on dementia and donated their brains to science after death. The team used GAGE-seq, which measures gene expression and 3D genome contacts in the same cell. They also integrated these measurements with spatial transcriptomic maps of intact tissue. Together, these complementary data allowed the researchers to relate 3D genome organization to gene regulation and place disease-associated molecular and cellular changes within their broader tissue context.

“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.”

A key computational advance was Hicformer, an AI model that combines DNA sequence, broad genome-folding features and local 3D contact maps to predict gene activity in different kinds of cells. Xinyue Lu, a doctoral student in Computational Biology who co-led the research, described Hicformer as a computational test bed for asking how altered genome folding may change 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.”

Researchers found that large active and inactive regions of the genome, known as compartments, were less clearly separated in cells from people with Alzheimer’s, a pattern the team calls “increased compartment mingling.” Multiple kinds of brain cells showed fewer short-range contacts and more long-range contacts, and greater compartment mingling was associated with lower overall gene activity. Contacts between genes and nearby regulatory elements that help control gene activity also weakened, while some midrange contacts strengthened. These architectural alterations were linked to reduced neuronal and synaptic programs, altered metabolic and stress responses, and senescence-related programs in microglia.

By mapping these changes across intact brain tissue, the researchers found that this reorganization of the genome was linked to changes in gene activity and in how brain cells were organized. The findings identify 3D genome organization as an important layer of Alzheimer’s biology and provide a framework for future experiments to determine which changes in genome structure contribute directly to the disease and whether they could reveal new therapeutic targets.