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 improved directions for treatment.

In a paper published in Science, researchers from the three institutions and their collaborators show that the 3D genome architecture is organized differently in certain brain cells from people with Alzheimer's disease, uncovering a previously underexplored layer of the disease's biology. The research team linked genome folding to gene activity and brain tissue organization in Alzheimer's disease through 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 in CMU's School of Computer Science, 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 multiscale view, researchers analyzed postmortem tissue from the prefrontal cortex obtained from individuals with and without Alzheimer's disease who 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, and 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 in 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 in the study 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 computational biology doctoral student 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 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.

This 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. Additional Pitt authors included doctoral students Alexander K. Kunisky and Jude Baroudi, post-baccalaureate research fellows Sahar and Sahel Ghorbanikalateh, and visiting scholar Shihan Wang. Zhijun Duan, a research associate professor, co-led the research from the University of Washington. The team also 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.