Summary: Researchers have mapped over 830,000 brain immune cells, discovering a protective subtype of microglia that expands as Alzheimer’s disease progresses. Driven by the TREM2 molecular pathway, these cells actively help clear harmful material from the brain. The findings provide a new roadmap for developing therapies focused on strengthening the brain’s natural immune defenses rather than targeting amyloid plaques alone.
Key Facts:
- Unprecedented Scale: The study analyzed over 830,000 myeloid-origin immune cells from 1,607 donors, providing the most detailed reference to date of immune cell changes across aging and disease.
- Protective Microglia Subtype: A specific, disease-associated subtype of microglia becomes more abundant as Alzheimer’s advances, acting to protect the brain by engulfing and clearing harmful material.
- Crucial Molecular Pathway: The beneficial, protective effects of these immune cells rely entirely on a molecular signaling pathway involving the proteins TREM2, MITF, and GPNMB.
Source: Mount Sinai Hospital / Mount Sinai School of Medicine
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. Now, a groundbreaking study published in Nature Genetics provides the most comprehensive map to date of these cells.
Researchers from the Icahn School of Medicine at Mount Sinai have identified a protective subtype of brain immune cell that expands as Alzheimer’s disease progresses, 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.
Led by Donghoon Lee, PhD, and Panos Roussos, MD, PhD, the team analyzed more than 830,000 myeloid-origin immune cells of the brain. This included microglia—the brain’s resident immune cells—and perivascular macrophages, which are crucial for modulating immune responses. The cells were sourced from the prefrontal cortex of 1,607 donors spanning a wide range of ages and Alzheimer’s disease pathology stages.
By profiling brain tissue at this unprecedented scale, the team identified six subclasses comprising 13 distinct subtypes of myeloid cells, characterizing how these populations adapt during aging and disease progression.
Crucially, the researchers identified a disease-associated subtype of microglia that becomes increasingly abundant as Alzheimer’s disease advances. Rather than contributing to neurodegeneration, 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 strictly on TREM2 signaling.
“Our study provides the clearest picture yet of how the brain’s immune cells adapt during aging and Alzheimer’s disease,” said Donghoon Lee, PhD, Assistant Professor of Genetics and Genomic Sciences and Psychiatry 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.”
Beyond identifying this protective microglial population, the study helps explain why genetic variants in immune-related genes such as TREM2 and APOE increase Alzheimer’s risk. Ultimately, the findings provide a roadmap for developing therapies that strengthen the brain’s natural immune defenses.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease research news
Author: Elizabeth Dowling (Media Contact)
Source: The Mount Sinai Hospital / Mount Sinai School of Medicine
Contact: Elizabeth Dowling – The Mount Sinai Hospital / Mount Sinai School of Medicine
Image: Graphical abstract credit goes to Mount Sinai Health System
Original Research: Peer-Reviewed Publication “Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease” by Donghoon Lee, Panos Roussos, et al. Nature Genetics
DOI: 10.1038/s41588-026-02716-6
