Scientists have uncovered significant biological changes in the human brain that begin around midlife, offering new insights into why aging increases the risk of diseases like Alzheimer’s. Published in the journal Science, the research reveals that between the ages of 50 and 75, the brain undergoes a transformation in its immune cells, which become more inflammatory. In addition, the cells that help maintain the blood-brain barrier weaken, and the three-dimensional structure of the genome—how DNA is folded inside the cell—begins to break down. These changes may contribute to the decline in brain function associated with aging. To reach these conclusions, researchers used advanced techniques to study gene regulation and the three-dimensional organization of the genome in individual cells from the hippocampus, a brain region crucial for learning and memory. By examining tissue samples from people of various ages, the team created one of the most comprehensive maps to date of how genetic regulation changes as the brain ages. One of the most striking findings was the transformation of microglia, the brain’s immune cells. Normally, microglia originate during fetal development and remain in the brain throughout life. However, the study found that starting around age 50, these original microglia begin to decline and are replaced by cells that resemble blood-borne immune cells. These new cells showed signs of increased inflammation, which could contribute to the chronic inflammation seen in older brains and possibly play a role in neurodegenerative diseases. The researchers also observed a decline in cells that support the blood-brain barrier, a protective layer that prevents harmful substances in the bloodstream from entering the brain. Additionally, they found that the three-dimensional structure of the genome—where DNA is folded within the cell—became less organized with age. This folding is essential for controlling which genes are active, and its disruption may affect brain function as people grow older. These findings suggest that brain aging is not a simple, gradual decline but a complex process involving multiple systems, including immune function, blood vessels, neurons, and genome structure. Understanding these changes could lead to new treatments aimed at preserving brain health over a person’s lifetime. The study is part of a broader, decade-long initiative by the National Institutes of Health called the 4D Nucleome program, which explored how the spatial arrangement of the genome influences biological processes.