DNA folding patterns shift in Alzheimer's brain cells and with aging

Inside every cell's nucleus, DNA does not sit as a loose tangle. It folds into a specific 3D shape, and that shape helps control which genes get switched on or off. A new set of studies, funded in part by the National Institutes of Health's 4D Nucleome program, examined whether this folding pattern changes in Alzheimer's disease and in ordinary aging.

One study, led by researchers at the University of Pittsburgh, the University of Washington, and Carnegie Mellon University, examined postmortem brain tissue from 20 people age 75 or older: 10 with Alzheimer's disease and 10 without. This study focused on the prefrontal cortex, a brain region known to undergo major changes in Alzheimer's. A second, related study looked at aging rather than disease, examining the hippocampus, the brain region central to forming and recalling memories, in a team led by researchers at the University of California, Irvine, and the University of California, San Diego. Both studies appeared in the same package of papers in the journal Science on July 23, 2026.

In a healthy cell, DNA divides roughly into two kinds of packing. Some stretches are bundled tightly, keeping the genes inside hard to reach and inactive. Other stretches are packed more loosely, keeping their genes accessible and active. Normally these two zones stay largely apart from each other inside the nucleus, like oil and water.

The Alzheimer's study found that in cells from people with the disease, this separation broke down: DNA from the two different packing types mingled together more than it did in cells from people without Alzheimer's. The researchers also found that distant stretches of the DNA sequence were more often positioned close together in Alzheimer's cells, while neighboring stretches were less often close together, a reversal of the usual pattern. To reach this conclusion, the team used a technique called GAGE-seq, which reads out gene activity and 3D chromatin structure from the same individual cells, and applied it across roughly 23,800 brain cells. They also combined this with additional techniques that map where chromatin is more or less accessible and where genes are expressed within intact tissue, and used a computational tool called Hicformer to test whether 3D genome structure could predict which genes changed activity in disease.

The aging study found a related but distinct pattern using hippocampus tissue: an overall loss of 3D genome organization with age, alongside age-related shifts in gene activity and in chemical marks on DNA. Taken together, the two studies point to a common theme, that both Alzheimer's disease and aging, which is itself the biggest known risk factor for Alzheimer's, involve some breakdown in how DNA is packaged inside the nucleus.

The researchers connected the chromatin mingling to actual changes in which genes were switched on or off. In general, greater mingling was associated with reduced gene activity, and this drop was especially pronounced in genes involved in several processes that help neurons function. But the pattern was not uniform: activity in genes involved in producing cellular energy and in making RNA actually increased alongside greater chromatin mingling.

The Alzheimer's study also reported that these effects varied by cell type, identifying disease-associated alterations in chromatin looping and genome organization linked to gene expression changes in specific populations of excitatory neurons, inhibitory neurons, and astrocytes. Jian Ma of Carnegie Mellon University, one of the study's leaders, said that "Alzheimer's disease cannot be understood one layer at a time," adding that "the genome's 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity." The aging study's authors suggested that the loss of 3D genome organization they observed with age may contribute to brain inflammation and dysfunction.

The idea that genome folding matters for Alzheimer's is not entirely new. A 2018 review noted that changes in chromatin topology, the physical arrangement of DNA within the nucleus, had already been observed in cultured cells expressing Alzheimer's-linked mutant proteins, and that proteins responsible for organizing the genome show altered expression and location in the Alzheimer's brain. That review also noted that evidence on how these structural changes affect transcription has not been fully agreed upon; some studies present conflicting findings on the extent and direction of transcriptional change in Alzheimer's and aging. A separate dataset built from Hi-C sequencing, a method for mapping which parts of the genome sit near each other in 3D space, on postmortem prefrontal cortex tissue from Alzheimer's patients, cognitively normal elderly people, and young individuals similarly found differences in chromatin loops and genome organization between the groups, and highlighted genes such as BIN1 as sitting under particularly intensive regulatory activity.

The new studies add higher resolution and single-cell detail to this picture, but the researchers themselves frame the work as raising further questions rather than closing them. The NIH's summary of the findings states plainly that more research is needed to determine how these organizational changes affect gene activity and cell health going forward. The relationship between chromatin structure and Alzheimer's has also, by the earlier review's account, historically produced inconsistent results across different studies, a caveat that applies to interpreting how firmly established any single mechanism is at this stage.