Brain immune cell map explains how defenses shift during Alzheimer’s progression

The brain’s immune cells are increasingly recognized as key players in Alzheimer’s disease, but exactly how they change as the disease develops has remained unclear. A new study published in Nature Genetics provides the most comprehensive map to date of these cells, identifying a protective subtype of brain immune cells that expands as Alzheimer’s disease progresses and uncovering the molecular pathway that enables these cells to help defend the brain. The findings offer new insights that could inform future Alzheimer’s therapies.

Researchers from the Icahn School of Medicine at Mount Sinai, led by Donghoon Lee, assistant professor of genetics and genomic sciences and psychiatry, and Panos Roussos, Mount Sinai professor of translational psychiatry, analyzed more than 830,000 myeloid-origin immune cells of the brain—including microglia, the brain’s resident immune cells, and perivascular macrophages, cells crucial for modulating the brain’s immune response—from the prefrontal cortex of 1,607 donors spanning the lifespan and representing a wide range of Alzheimer’s disease pathology. By profiling brain tissue at an unprecedented scale, the team identified six subclasses comprising 13 distinct subtypes of myeloid cells and characterized how these populations change during aging and disease progression.

The researchers identified a disease-associated subtype of microglia that becomes increasingly abundant as Alzheimer’s disease advances. Rather than contributing to damage, these cells appear to play a protective role by increasing their ability to engulf and clear harmful material from the brain. The study further identified a molecular pathway involving the proteins TREM2, MITF and GPNMB that is required to maintain this protective microglial state. Experiments in both human tissue and mouse models demonstrated that the beneficial effects of these cells depend on TREM2 signaling.

Beyond identifying this protective microglial population, the study provides the most detailed reference to date of how the brain’s immune cells change across the lifespan and throughout Alzheimer’s disease. The findings help explain why genetic variants in immune-related genes such as TREM2 and APOE increase Alzheimer’s risk and provide a roadmap for developing therapies that strengthen the brain’s natural immune defenses rather than focusing solely on amyloid plaques.

“Our study provides the clearest picture yet of how the brain’s immune cells adapt during aging and Alzheimer’s disease,” said Lee, assistant professor of genetics and genomic sciences and psychiatry at the Icahn School of Medicine at Mount Sinai and first and corresponding author of the paper. “By identifying the specific immune cells that appear to protect the brain—and the molecular signals they rely on—we have uncovered potential new targets for therapies aimed at slowing Alzheimer’s disease progression.”

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Robert Egan

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