Aging and Brain Changes: Implications for Alzheimer’s

At around 50 years old, the brain’s memory center begins exchanging its established immune cells for more inflammatory ones, according to a new study. This finding may explain how normal aging can lead to conditions like dementia, particularly Alzheimer’s disease.

Dr. Furhan Qureshi, a board-certified internal medicine physician, expressed surprise at the discovery. “In med school, we learned that the brain’s main immune cells were lifelong residents, appearing before birth and renewing themselves in the brain,” Qureshi told Newsweek. “However, this study reveals that around age 50, the hippocampus starts replacing them with more inflammatory cells, possibly from the blood. This significantly alters our understanding of the brain’s immune system.”

Qureshi highlighted that these findings could change the scientific perspective on Alzheimer’s origins. “Inflammation is prevalent in Alzheimer’s-affected brains, but its starting point was unclear,” he said. “This study suggests the changes are part of the normal aging process, initiating in midlife long before symptoms emerge.”

Study Findings

The study, funded by the National Institutes of Health, focused on the hippocampus, essential for learning and memory. A team from the University of California, San Diego, the New York Genome Center, and the University of California, Irvine, analyzed postmortem hippocampal tissue from 40 neurologically healthy adults aged 20 to 95. They used advanced single-cell techniques to conduct their research.

The researchers discovered that microglia, the main immune cells in the brain, decline steadily between ages 50 and 75. As these cells decrease, they are replaced by those with stronger inflammatory signals, resembling monocytes. Monocytes are immune cells usually found circulating in the blood, not the brain.

This finding challenges long-standing beliefs about microglia formation and maintenance. Researchers previously thought microglia formed during embryonic development and remained in the brain, continually renewing themselves without external replacement.

The shift in cell types was detected by combining standard gene-activity measurements with techniques that map the genome’s three-dimensional structure and chemical modifications, known as the epigenome. This combination revealed cell identity and origin changes that gene activity measurements alone would miss.

The study also noted early signs of decline in cells supporting the blood-brain barrier, which regulates what enters the brain from the bloodstream.

Implications

Aging is the leading risk factor for neurodegenerative diseases, with the hippocampus being particularly susceptible. Researchers estimate that about 42 percent of Americans over age 55 will eventually develop dementia.

While previous studies linked aging to increased inflammatory gene activity, gene expression alone did not fully explain the decline drivers.

Dr. Ankit Chawla, specializing in longevity and functional medicine, stated that the findings align with his field’s observations. “From a longevity standpoint, the immune system plays a crucial role in the processes driving aging, including in the brain,” Chawla told Newsweek. “It’s not surprising to see this as a factor in the aging brain.”

The study also found that aging weakens the genome’s overall three-dimensional organization across brain cell types. There is a noted loss of astrocytes, essential cells that support brain signaling and metabolism.

Newsweek contacted the study’s authors for additional insights.

Reference: Zemke, N. R., et al. (2026). Epigenetic and 3D genome reprogramming during the aging of the human hippocampus. Science. https://doi.org/10.1126/science.adt8307. Contact Newsweek editors on this story: Kara Dolman and Emma Lee-Sang.