3D Genome Architecture Altered in Alzheimer’s Disease Brain Cells

Researchers have uncovered that the three-dimensional organisation of the genome is altered in brain cells affected by Alzheimer’s disease, a Carnegie Mellon University-led study found. Published by an international team combining single-cell analysis, spatial transcriptomics, and artificial intelligence, the findings link genome folding changes to altered gene activity in the prefrontal cortex.

How 3D Genome Folding Influences Alzheimer’s Disease Pathology

Scientists investigated how the genome folds inside cells and how this structural organization influences gene activity, moving beyond examining genes in isolation. According to Carnegie Mellon University, the team analyzed postmortem tissue from the prefrontal cortex of individuals with and without Alzheimer’s disease who participated in a long-term dementia study.

The research team utilized GAGE-seq, a technique measuring gene expression and three-dimensional genome contacts within the same cell. These measurements were integrated with spatial transcriptomic maps of intact brain tissue to examine molecular changes in their native environment.

AI Model Hicformer Identifies Compartment Mingling in Brain Cells

To predict gene activity, researchers developed an artificial intelligence model named Hicformer. According to the study, Hicformer combines DNA sequence data with information on genome folding and local three-dimensional contact maps.

The AI model revealed that the separation between active and inactive regions of the genome becomes less distinct in Alzheimer’s-affected brain cells. Researchers describe this phenomenon as ‘increased compartment mingling.’ Furthermore, these affected cells displayed fewer short-range genome contacts and more long-range interactions, correlating with reduced overall gene activity.

Connecting Chromosome Structure to Neuronal and Metabolic Changes

Structural genome alterations directly tie into reduced neuronal and synaptic programs, altered metabolic and stress responses, and senescence-related programs in microglia, according to the findings. Hansruedi Mathys, assistant professor of neurobiology at the University of Pittsburgh’s Department of Neurobiology, noted that the work establishes these higher-order chromatin alterations alongside the seven million Americans currently affected by the condition.

“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.”

Providing a Framework for Future Therapeutic Targets

The paired view of gene activity and genome folding across several kinds of brain cells revealed a consistent signature of 3D genome reorganization, according to Yang Zhang, a project scientist in Carnegie Mellon University’s Computational Biology Department and co-lead author of the study. This signature helps prioritize regulatory regions for future mechanistic investigation.

The findings offer a structural framework for upcoming studies to evaluate whether genome structure changes contribute directly to Alzheimer’s disease pathology and whether they can serve as targets for new treatments.

Frequently Asked Questions

What is 3D genome organisation in Alzheimer’s disease?

It refers to how DNA folds inside brain cells. Researchers found that this three-dimensional folding is altered in Alzheimer’s patients, affecting how genes are expressed.

What is GAGE-seq?

GAGE-seq is a laboratory technique used by researchers to measure both gene expression and three-dimensional genome contacts within the exact same individual cell.

What role does AI play in this research?

Researchers developed an artificial intelligence model called Hicformer to predict gene activity by combining DNA sequence data with genome folding and spatial contact maps.

How many people are affected by Alzheimer’s disease in the US?

According to study authors from the University of Pittsburgh, the condition currently affects seven million Americans.