Scientists Find a New Layer of Alzheimer’s Hidden in the Genome

When people talk about the biology of Alzheimer’s disease, the conversation almost always centers on two culprits: amyloid-beta plaques and tau tangles. A new study from Carnegie Mellon University, the University of Pittsburgh School of Medicine, and the University of Washington suggests there’s a third, much less explored layer to the story, not in what genes a cell has, but in how those genes are physically folded and arranged inside the nucleus.

DNA Isn’t Just a String of Letters

DNA doesn’t sit inside a cell as a simple straight strand. It folds into an intricate three-dimensional structure, looping and packing itself into a compact shape that determines which genes are physically accessible to the cellular machinery that turns them on or off. That 3D organization is sometimes called the genome’s architecture, and it’s now emerging as its own layer of biology, one that can go wrong independently of the DNA sequence itself.

“Alzheimer’s disease cannot be understood one layer at a time,” said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology at 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.”

Combining Three Layers of Data

To investigate this, the team examined postmortem prefrontal cortex tissue from people with and without Alzheimer’s disease who had taken part in a long-term dementia study and donated their brains for research afterward. They used a technique called GAGE-seq, which can measure both gene expression and 3D genome contacts within the very same individual cell, letting researchers see, cell by cell, how a gene’s activity relates to how its DNA is physically folded.

Those single-cell measurements were then layered with spatial transcriptomic maps, which preserve information about exactly where in the intact brain tissue different genes are active. Combining the two let the researchers connect genome architecture, gene regulation, and tissue-level context all at once, rather than studying each in isolation.

An AI Model Built to Test the Connection

The team also built a deep learning model called Hicformer, which combines raw DNA sequence information with broader patterns of genome folding and detailed maps of which DNA regions physically touch one another. Fed these inputs, Hicformer predicts gene activity across different brain cell types, effectively acting as a computational test bed for asking how a change in genome folding might translate into a change in gene activity, according to Xinyue Lu, a doctoral student in Computational Biology who co-led the research.

“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.”

When Genome Boundaries Blur

Large sections of the genome are normally sorted into fairly distinct “active” and “inactive” zones known as compartments. In brain cells from people with Alzheimer’s disease, those boundaries were noticeably less sharp, a pattern the researchers describe as increased compartment mingling. Several types of brain cells also showed fewer contacts between nearby DNA regions and more contacts between regions that are normally far apart, along with weaker connections between genes and the regulatory elements that help switch them on or off.

Notably, cells with more of this compartment mingling tended to have lower overall gene activity. These structural shifts were linked to reduced activity in gene programs involved in neurons and synapses, changes in metabolism and cellular stress responses, and, in microglia, the brain’s resident immune cells, links to senescence-related gene programs.

Adding to the Picture, Not Replacing It

“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.”

Importantly, this isn’t a competing explanation for Alzheimer’s, it’s an additional one. Chromatin, the material made of DNA and its associated proteins that packages the genome inside a cell, now joins amyloid and tau as part of the disease’s broader molecular landscape.

Where This Could Lead

When the researchers mapped these molecular changes across intact brain tissue, the genome reorganization was tied not just to altered gene activity, but to differences in how brain cells were physically arranged within the tissue itself. That gives the field a new, testable framework: future studies can now ask whether specific structural changes actively drive Alzheimer’s progression, and whether any of the newly flagged regulatory regions could eventually become targets for treatment.

The research, supported by grants from the National Institutes of Health, also included collaborators from the Broad Institute of MIT and Harvard, UCLA, and the Rush Alzheimer’s Disease Center. The study was published in Science.

Sources

·         Press release (Carnegie Mellon University, quoting Pitt’s Dr. Mathys who led the Pitt arm of the study): AI, Single-Cell Technology Reveal How 3D Genome Differs in People With Alzheimer’s Disease

·         Original paper: Zhang et al., “Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease,” Science, 2026

Source: Scientists Find a New Layer of Alzheimer’s Hidden in the Genome