DNA is not simply stored as a straight sequence inside the nucleus. It is folded, looped and packed into a complex three-dimensional structure that helps determine which genes are active and which remain silent.

New research suggests that this organization becomes disrupted in Alzheimer’s disease and also changes as the brain ages. The findings point to genome structure as another important layer connecting aging, gene activity and neurological disease.

Looking Beyond DNA Sequence

Scientists already know that health can be influenced by changes in DNA sequence and by chemical marks attached to DNA.

But the physical arrangement of DNA inside the nucleus also matters. A research team examined whether this three-dimensional organization changes in Alzheimer’s disease and whether those changes are linked to disruptions in gene activity.

The study focused on postmortem brain tissue from people aged 75 and older. Ten had Alzheimer’s disease and ten did not.

Researchers analyzed several cell types from the prefrontal cortex, a brain region that undergoes major changes in Alzheimer’s.

DNA Folds Differently in Alzheimer’s

The scientists found clear structural differences between cells from the two groups. In Alzheimer’s samples, distant sections of DNA were more likely to come into contact with one another, while neighboring regions interacted less often.

This suggests that the normal organization of the genome had become less orderly. The changes were driven by rearrangements in chromatin, the combination of DNA and proteins that fills the nucleus.

Some chromatin is tightly packed and contains genes that are largely inactive. Other regions are more open and contain genes that are easier for the cell to use. Normally, these different types remain relatively separated. In Alzheimer’s cells, however, they mixed together more than usual.

Neuron-Related Genes Became Less Active

The structural changes were not random. Greater chromatin mixing was linked to reduced activity in several groups of genes involved in normal neuronal function. At the same time, genes connected with energy production and RNA processing became more active.

These patterns suggest that altered DNA folding may contribute to the molecular changes already observed in Alzheimer’s disease. The study does not prove that disrupted genome organization causes the disease, but it adds another possible mechanism through which brain cells may lose normal function.

Aging Shows Similar Patterns

A separate study examined cells from the hippocampus, a brain region essential for memory formation and recall.

Researchers found that the three-dimensional organization of the genome became less structured with age. These changes occurred alongside shifts in gene activity and in chemical modifications to DNA. Together, the results suggest that aging itself may gradually weaken the organization of the genome. That loss of structure could influence inflammatory pathways and contribute to declining brain function over time.

Why Genome Structure Matters

According to study leader Jian Ma, Alzheimer’s cannot be understood by examining only one biological layer at a time. He argues that the three-dimensional structure of the genome acts as a fundamental regulatory system linking DNA sequence with gene activity. That perspective may help explain why Alzheimer’s involves such widespread changes across many genes and cellular processes.

Rather than focusing only on mutations or individual genes, researchers may need to consider how the entire genome is physically arranged.

A New Direction for Research

The findings raise several important questions. Scientists still need to determine whether changes in DNA organization are a cause of cellular dysfunction, a consequence of disease, or both. It is also unclear whether the process can be slowed, prevented or reversed. Future studies may help identify which structural changes appear earliest and whether they could become useful markers of brain aging or disease progression. The broader message is that Alzheimer’s may involve not only changes in what DNA contains, but also changes in how that DNA is physically organized inside the cell.

Understanding that hidden layer could offer a more complete picture of how aging reshapes the brain and why some cells become vulnerable to neurodegeneration.