Scientists have uncovered a new aspect of Alzheimer's disease, revealing that it is linked to how DNA is organized in three dimensions within brain cells. A study published in the journal Science shows that the way the genome is folded differs in brain cells from individuals with Alzheimer's compared to those without the disease. These structural changes in DNA are connected to altered gene activity and changes in the brain's cellular organization. The research combined single-cell technology, spatial mapping of brain tissue, and a new deep learning model called Hicformer to reveal these complex changes in detail. The study used postmortem brain tissue samples from the prefrontal cortex, a region involved in decision-making and behavior, taken from both individuals with and without Alzheimer's. Researchers employed a technique called GAGE-seq, which simultaneously measures gene expression and three-dimensional interactions of DNA within individual cells. This method was combined with spatial transcriptomic maps, which show where specific genes are active in different parts of the brain tissue. This approach helped the team connect changes in DNA folding with gene regulation and identify where Alzheimer's-related changes occurred in the surrounding cells. The research highlights that changes in chromatin, the complex of DNA and proteins that packages genetic material inside cells, should be considered an important part of Alzheimer's disease. The team found several consistent differences in the genome structure of brain cells from Alzheimer's patients, including "increased compartment mingling." Normally, large sections of the genome are organized into distinct active and inactive regions. In Alzheimer's cells, these boundaries are less clear, suggesting a more chaotic genome structure. These structural changes were linked to reduced activity in genes involved in neurons and their connections (synapses), as well as changes in metabolism and how cells respond to stress. Additionally, the study found that microglia, immune cells in the brain responsible for maintaining health and responding to injury, showed signs of senescence, a state of cellular aging. These findings suggest that Alzheimer's disease affects not only neurons but also the brain's immune system. The study was supported by the National Institutes of Health and involved researchers from several institutions, including the Broad Institute of MIT and Harvard, the University of California, Los Angeles, and the Rush Alzheimer's Disease Center.