Alzheimer’s may affect more than brain cells — scientists discover DNA’s 3D shape is changing in ways that could reveal hidden causes of memory loss

Alzheimer’s disease may be altering the brain in a way that has received far less attention than the buildup of amyloid plaques and tau tangles.

A new study has found that the three-dimensional organisation of DNA changes in several types of brain cells affected by Alzheimer’s disease. These changes appear to influence how genes are switched on and off, offering scientists a new way to investigate how the condition develops.

Researchers from Carnegie Mellon University, the University of Pittsburgh and the University of Washington combined advanced genetic testing, spatial mapping and artificial intelligence to examine the structure of DNA inside individual brain cells.


Their findings suggest that Alzheimer’s is not only associated with changes in proteins or damaged neurons. It may also disturb the way genetic material is folded and arranged inside the cell.

The study was published in Science and could help researchers identify new biological pathways involved in Alzheimer’s disease.

DNA’s shape may be as important as its genetic code

DNA is often described as the instruction manual of life. But the genetic code is only part of the story.

Inside every cell, DNA is tightly folded and organised with the help of proteins. This arrangement, known as chromatin structure, determines which sections of DNA are accessible to the cell’s machinery.

Genes that are accessible can be activated more easily, while tightly packed sections are often less active. In this way, the physical organisation of DNA helps control the behaviour and function of a cell.

The new research suggests that this arrangement becomes disrupted in brain cells affected by Alzheimer’s.

Scientists examined postmortem tissue from the prefrontal cortex, a region involved in thinking, decision-making and other higher brain functions. The samples came from people with and without Alzheimer’s disease who had participated in a long-term dementia research programme.

The team discovered that the genome was folded differently in Alzheimer’s-affected cells. This reorganisation was linked to changes in gene activity and the way brain cells were arranged within the surrounding tissue.

The results point to a previously underexplored layer of Alzheimer’s biology: the relationship between the shape of DNA and the activity of genes.

Researchers identify widespread changes in genome organisation

The scientists found that large areas of the genome appeared less clearly separated in Alzheimer’s-affected cells.

Normally, active and inactive sections of DNA are organised into distinct compartments. In the Alzheimer’s samples, these boundaries appeared less defined, creating what researchers described as increased “compartment mingling”.

The study also identified changes in the way different parts of the genome interacted with one another.

Some nearby DNA regions showed weaker connections, while certain sections located farther apart formed stronger contacts. These changes may affect how genes communicate with regulatory elements that control their activity.

The researchers found that these structural differences were associated with reduced activity in gene programmes linked to neurons and synapses.

Synapses are the communication points through which brain cells exchange signals. Their proper function is essential for memory, learning and normal thinking. Disruption in these systems is a major feature of Alzheimer’s disease.

The altered DNA organisation was also connected with changes in metabolism and cellular stress responses. In microglia — the immune cells of the brain — the researchers found links to programmes associated with cellular ageing, or senescence.

These findings do not prove that altered DNA folding directly causes Alzheimer’s. However, they show that genome organisation changes alongside other molecular and cellular features of the disease.

Artificial intelligence helps connect DNA structure with gene activity

One of the most important parts of the study was the use of artificial intelligence to interpret the complex data.

The researchers developed a deep learning model called Hicformer. The system was designed to examine DNA sequence information together with patterns showing which parts of the genome physically interact.

By combining these inputs, the model can predict gene activity across different types of cells.

This approach gave scientists a way to examine not only which genes were active, but also how the physical arrangement of DNA may have influenced that activity.

The team also used GAGE-seq, a technique that measures gene expression and three-dimensional genome contacts within the same cell. This allowed researchers to connect changes in DNA folding directly with changes in gene behaviour.

Spatial transcriptomic data added another layer of information. It showed where molecular changes were occurring inside intact brain tissue, helping the scientists understand how individual cells were affected within their wider environment.

According to the researchers, this combined approach is important because Alzheimer’s disease does not affect every brain cell in the same way.

Neurons, support cells and immune cells can respond differently to the disease. Studying genome structure at the single-cell level may therefore reveal changes that would be missed in an analysis of a whole piece of brain tissue.

The researchers said the work could help identify regulatory regions that deserve further investigation as possible targets for future treatments.

A new direction beyond amyloid and tau

Amyloid-beta plaques and tau tangles remain two of the best-known biological features of Alzheimer’s disease. They have shaped much of the research into the condition and have influenced the development of several treatments.

The new findings do not replace those established areas of study. Instead, they suggest that Alzheimer’s may involve additional layers of biological disruption.

Changes in chromatin and genome folding could influence how brain cells respond to stress, maintain connections and regulate important functions.

If certain DNA-organisation changes appear early in the disease, they might eventually help scientists understand how Alzheimer’s begins or progresses. If they occur later, they could still provide clues about why brain cells become damaged.

The next step will be to determine which changes are consequences of the disease and which might contribute to driving it.

Researchers will also need to establish whether the genome alterations are specific to Alzheimer’s or whether similar patterns appear in other forms of dementia and brain ageing.

Another important question is whether these changes can be reversed. If genome folding contributes to harmful gene activity, future treatments might attempt to restore healthier patterns of regulation.

That possibility remains speculative. The current study provides a biological framework for further research rather than an immediate treatment or diagnostic test.

Still, the discovery offers a new perspective on a disease that affects millions of people worldwide. It suggests that the brain’s genetic material may not simply carry instructions that become disrupted during Alzheimer’s. The physical arrangement of those instructions may also change.

By combining genetic data, tissue mapping and AI, scientists are beginning to see Alzheimer’s as a condition involving several interconnected systems — from proteins and cells to the three-dimensional structure of DNA.

The research could eventually help identify new mechanisms behind memory loss and other symptoms, while opening additional paths for drug development.

For now, the main message is clear: understanding Alzheimer’s may require scientists to look not only at what is written in the genome, but also at how the genome is folded inside the brain’s cells.

Frequently asked questions

1. What new Alzheimer’s discovery did scientists make?

Researchers found that the three-dimensional organisation of DNA changes in several types of brain cells affected by Alzheimer’s disease. These changes were linked to altered gene activity.

2. What is genome folding?

Genome folding is the way DNA is organised and packed inside a cell. Its three-dimensional structure helps determine which genes can be activated and which remain less accessible.

3. Did the study prove that DNA changes cause Alzheimer’s?

No. The research identified a strong association between altered genome organisation and Alzheimer’s disease, but further studies are needed to determine whether these changes help cause the disease or result from it.

4. How could this research help future Alzheimer’s treatments?

The findings may help scientists identify regulatory regions and biological pathways involved in Alzheimer’s. These could eventually become targets for new medicines, although practical treatments are still a long way off.