The NIH Common Fund’s 4D Nucleome (4DN) program supports research into how the genome’s three-dimensional organization changes over time, with the goal of understanding how DNA folding is affected by aging and disease. The program also supports the development of advanced technologies for studying genome organization inside cells.

A 4DN-funded research team led by Drs. Hansruedi Mathys of the University of Pittsburgh, Zhijun Duan of the University of Washington, and Jian Ma of Carnegie Mellon University investigated how 3D genome organization changes in Alzheimer’s disease. Their findings, published in Science on July 23, 2026, examined postmortem prefrontal cortex tissue from 20 individuals aged 75 and older, including 10 people with Alzheimer’s and 10 without the disease.

The researchers identified significant differences in DNA folding between the two groups. In Alzheimer’s cells, distant regions of DNA were more likely to come into physical contact, while neighboring regions interacted less frequently. These changes were linked to alterations in chromatin organization—the way DNA and proteins are packaged inside the nucleus.

The study found that normally distinct regions of tightly packed, inactive chromatin and more open, active chromatin became increasingly mixed in Alzheimer’s disease. Greater chromatin mixing was generally associated with reduced activity of genes involved in important neuronal functions, while some genes related to energy production and RNA synthesis showed increased activity.

A separate 4DN-supported study examined how aging affects genome organization in cells from the hippocampus, a brain region essential for memory. Researchers from the University of California, Irvine, and the University of California, San Diego found that 3D genome organization gradually becomes less structured with age. These changes were accompanied by alterations in gene activity and DNA-associated chemical marks, potentially contributing to inflammation and impaired brain function.

Together, the findings suggest that both aging and Alzheimer’s disease may involve substantial changes in the way DNA is organized within the nucleus. Understanding these structural changes could provide new insights into how gene activity becomes disrupted and how brain cells lose their normal function during aging and neurodegenerative disease.

Source: https://www.nih.gov/news-events/nih-research-matters/dna-organization-changes-alzheimers-disease-aging