Scientists Discover New 3D Genome Layer in Alzheimer’s Disease

Scientists have uncovered a previously hidden structural layer of Alzheimer’s disease within the human genome, revealing how higher-order changes in 3D chromosome organization disrupt brain cell function, according to research published in Science.

Scientists from the University of Washington, the University of Pittsburgh School of Medicine, and Carnegie Mellon University’s School of Computer Science charted the three-dimensional structure of the genome using postmortem brain samples. The findings establish that higher-order chromatin alterations represent a component of the molecular pathology associated with Alzheimer’s disease, which affects seven million Americans.

“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. By integrating genome folding, cell state, and tissue context, the research team aimed to move past simply cataloging disease-associated changes and begin understanding how underlying mechanisms connect.

Mapping 3D Genome Structure with Single-Cell Technology

To build a multi-scale view of the brain, the research team analyzed postmortem tissue samples taken from the prefrontal cortex. The brain tissue came from individuals with and without Alzheimer’s disease who participated in a long-term dementia study and donated their brains for scientific research after death.

The investigators deployed GAGE-seq, a specialized technique that measures gene expression and 3D genome contacts within the exact same cell. They then combined these measurements with spatial transcriptomic maps of intact tissue. This complementary approach allowed scientists to link 3D genome organization directly to gene regulation and observe molecular shifts within their broader tissue environment.

“Our study represents a major advance in understanding what goes wrong in Alzheimer’s disease,” said Hansruedi Mathys, assistant professor of neurobiology at the University of Pittsburgh’s Department of Neurobiology, who directed the Pitt arm of the study. While the accumulation of amyloid-beta plaques and tau tangles remains a classic hallmark of the condition, the new data establishes higher-order chromatin alterations as another piece of the molecular puzzle.

AI Model Predicts Gene Activity From Chromosome Folding

A crucial computational breakthrough in the project involved the development of an artificial intelligence model named Hicformer. Created by researchers in Carnegie Mellon’s Ray and Stephanie Lane Computational Biology Department, the model combines DNA sequence data, broad genome-folding features, and local 3D contact maps to predict gene activity across various types of brain cells.

Xinyue Lu, a doctoral student in computational biology who co-led the research, noted that Hicformer functions as a computational test bed. The tool allows scientists to investigate how altered genome folding modifies 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 also co-led the study. Across multiple brain cell types, the paired view revealed a consistent signature of 3D genome reorganization, helping investigators prioritize specific regulatory regions for future therapeutic and mechanistic testing.

Increased Compartment Mingling and Lower Gene Activity

The analysis revealed that large active and inactive genomic regions, known as compartments, showed less distinct separation in cells from individuals with Alzheimer’s disease. The research team characterizes this pattern as increased compartment mingling.

Across several kinds of brain cells, this structural breakdown corresponded with fewer short-range contacts, an increase in long-range contacts, and lower overall gene activity. Furthermore, contacts between genes and nearby regulatory elements responsible for controlling gene activity weakened, pointing toward regulatory dysfunction in the diseased brain.