Researchers Identify 3D Genome Alterations as New Layer of Alzheimer’s Disease

Scientists from Carnegie Mellon University, the University of Pittsburgh School of Medicine, and the University of Washington have identified a previously overlooked biological layer in Alzheimer’s disease, reporting their findings in the journal Science. The research demonstrates that the three-dimensional organization of the genome is significantly altered in the brain cells of individuals with Alzheimer’s, providing a new framework for understanding the disease’s molecular pathology.

The study moves beyond the traditional focus on amyloid-beta plaques and tau tangles. Researchers combined single-cell sequencing technologies, spatial mapping of brain tissue, and a novel deep learning model to link changes in genome folding with shifts in gene activity and tissue organization.

“Alzheimer’s disease cannot be understood one layer at a time,” said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology at Carnegie Mellon University, who led 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 within a cell is not arranged as a simple linear strand but folds into a complex three-dimensional structure that dictates which genes are accessible. The team analyzed postmortem prefrontal cortex samples from participants in a long-term dementia study. They utilized GAGE-seq, a technique capable of measuring both gene expression and three-dimensional genome contacts within individual cells, and combined these data with spatial transcriptomic maps to preserve the location of gene activity within intact tissue.

Hansruedi Mathys, an assistant professor of neurobiology at the University of Pittsburgh, emphasized the significance of the findings. “Our study represents a major advance in understanding what goes wrong in Alzheimer’s disease,” Mathys said. “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 critical component of the research was Hicformer, an artificial intelligence model developed to investigate how genome structure influences cellular behavior. Hicformer integrates DNA sequence information with patterns of genome folding to predict gene activity across different cell types. Xinyue Lu, a doctoral student in computational biology who co-led the research, described the system as a computational test bed for exploring how alterations in genome folding might 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 also co-led the work. “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.”

The researchers observed that in Alzheimer’s cells, the boundaries between active and inactive regions of the genome, known as compartments, became less distinct, a pattern described as “increased compartment mingling.” This reorganization was associated with fewer interactions between nearby genomic sections and more contacts between distant regions. Cells exhibiting greater compartment mingling showed lower overall gene activity.

Additionally, the study found weaker interactions between genes and nearby regulatory elements, alongside stronger contacts across intermediate distances. These structural differences correlated with reduced activity in programs related to neurons and synapses, as well as changes in metabolism and cellular stress responses. Links to senescence-related programs were also observed in microglia, the immune cells responsible for maintaining brain health.

When mapped onto intact brain tissue, the molecular reorganization of the genome was connected not only to altered gene activity but also to differences in how brain cells are arranged. The findings establish three-dimensional genome organization as a significant layer of Alzheimer’s biology and provide a framework for testing which architectural changes may directly contribute to the disease.

Future research will investigate whether specific structural changes drive Alzheimer’s progression and whether affected regulatory regions could serve as targets for new therapies. The study was supported by grants from the National Institutes of Health, with additional contributions from researchers at the Broad Institute of MIT and Harvard, the University of California, Los Angeles, and the Rush Alzheimer’s Disease Center.