Alzheimer’s disease has long been described through the lens of neurons: the loss of synapses, the accumulation of amyloid-β plaques, and the formation of tau tangles. Yet the brain’s immune cells may determine whether this damage accelerates or is contained. A large-scale study published in Nature Genetics now offers one of the most detailed maps to date of human myeloid cells in the aging and Alzheimer’s brain. By analyzing 832,505 cells from the prefrontal cortex of 1,607 donors, researchers identified a disease-associated microglial state that expands as Alzheimer’s pathology advances and appears to mount a more active response against damaged material.
The study focuses on myeloid cells, a broad immune-cell family that includes microglia—the resident immune cells of the central nervous system—and perivascular macrophages, which occupy spaces surrounding blood vessels. These cells constantly monitor the brain, remove cellular debris, respond to injury, and communicate with neurons, astrocytes, endothelial cells, and other immune populations. Their behavior is highly adaptable. In healthy aging, this adaptability may help preserve tissue function, but in Alzheimer’s disease, myeloid cells can become chronically activated, lose efficiency, or contribute to inflammation. Understanding which cellular states are harmful, protective, or context-dependent has been a major challenge because human brain immune cells do not exist as a single uniform population.
To address that complexity, the investigators profiled individual cells from human prefrontal cortex samples spanning the lifespan and representing different degrees of Alzheimer’s neuropathology. Single-cell transcriptomics allowed them to measure patterns of gene activity in each cell rather than averaging signals across an entire tissue sample. The researchers organized the myeloid compartment into six broad subclasses and 13 transcriptionally distinct subtypes. This classification revealed that aging and disease progression are accompanied by coordinated changes in cell identity and activity, rather than by a simple increase or decrease in “inflammation.” Different myeloid populations appeared to follow distinct trajectories as pathology accumulated.
Among the most notable populations was a disease-associated microglial subtype marked by elevated expression of GPNMB. The abundance of these cells increased in association with Alzheimer’s pathology, suggesting that they are not merely a rare response to injury but part of a reproducible cellular transition in the diseased brain. The subtype was also enriched for genes linked to polygenic Alzheimer’s disease risk, connecting inherited susceptibility to a specific microglial program. Polygenic risk reflects the combined effects of many genetic variants, each of which may exert a small influence on disease probability. Finding that risk-associated signals converge in this microglial population provides a possible explanation for how genetic vulnerability is translated into altered immune behavior.
The researchers further reported evidence that the GPNMB-high microglia display increased phagocytic activity. Phagocytosis is the process by which immune cells engulf and digest extracellular debris, damaged structures, and aggregated proteins. In Alzheimer’s disease, efficient phagocytosis could help clear toxic material, although excessive or poorly regulated engulfment can also damage synapses and surrounding tissue. The study’s findings therefore point to a nuanced role for this state: the cells may represent an adaptive response that becomes more prominent as pathology grows, while their ultimate effects depend on the signals they receive and the molecular machinery that controls their activity.
One of the study’s central mechanistic findings involves MITF, a transcription factor that regulates gene expression by binding to specific DNA sequences and coordinating broader cellular programs. Through regulatory analyses, the investigators identified MITF as an upstream regulator required to maintain the GPNMB-associated microglial state. This suggests that the subtype is not defined simply by a passive reaction to plaque or tissue damage. Instead, it is actively stabilized by an underlying transcriptional network. Targeting such a network could be more precise than broadly suppressing inflammation, because it might allow researchers to enhance beneficial immune functions while avoiding the loss of essential surveillance and repair activities.
The study also examined how myeloid cells communicate with their surroundings. Cell–cell interaction analyses prioritized signaling pairs involving APOE and the receptors SORL1 and TREM2. APOE is a major lipid-transport protein in the brain and one of the strongest genetic risk factors for late-onset Alzheimer’s disease, particularly through the APOE ε4 variant. SORL1 participates in intracellular trafficking and the processing of receptors and protein cargo, while TREM2 is a microglial receptor that regulates survival, metabolism, migration, and responses to lipid-rich or damaged material. The identification of APOE–SORL1 and APOE–TREM2 signaling axes suggests that communication between extracellular lipid-handling systems and microglial receptors may influence how immune cells adapt during disease progression.
TREM2 emerged as especially important when the researchers examined the protective potential of the GPNMB-high microglial subtype in human and mouse models. The reported results indicate that the neuroprotective effects associated with this state depend on TREM2. In other words, the presence of the transcriptional program alone may not be sufficient; microglia must also retain TREM2-dependent signaling capacity to translate that state into protection for surrounding neural tissue. TREM2 has previously been linked to Alzheimer’s risk and to the ability of microglia to cluster around pathological lesions, adjust their metabolism, and respond to changes in the brain’s lipid environment. The new findings place that receptor within a broader human cellular framework involving aging, genetic susceptibility, transcriptional regulation, and intercellular communication.
The scale of the analysis is significant because human Alzheimer’s disease is biologically diverse. Patients differ in age, genetic background, disease duration, plaque and tau burden, vascular health, and the composition of their immune cells. Results from experimental models are indispensable, but mouse microglia do not always reproduce the molecular states found in human disease. By integrating a large human cohort with validation in human and mouse systems, the researchers were able to move from description toward mechanism. Their findings do not suggest that every activated microglial cell is beneficial, nor that increasing phagocytosis alone would be therapeutic. Instead, they identify a specific, genetically informed cell state whose activity appears to be shaped by MITF and whose protective function requires TREM2.
The work could influence how researchers approach Alzheimer’s therapies. Broad anti-inflammatory strategies may inadvertently suppress the immune functions needed to remove debris and protect vulnerable neurons. A more targeted approach would seek to reinforce beneficial microglial programs, improve the quality of phagocytic responses, or restore signaling through pathways such as TREM2 without triggering damaging inflammation. The study also emphasizes that microglia and perivascular macrophages are dynamic participants in disease, not simply bystanders reacting to neuronal decline. As Alzheimer’s research increasingly turns toward the interactions among immune cells, lipids, blood vessels, and neurons, the newly defined cellular landscape may help guide the search for treatments tailored to the biological state of an individual brain.
Subject of Research: Human myeloid cells, including microglia and perivascular macrophages, in aging and Alzheimer’s disease
Article Title: Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease
Article References: Lee, D., Vicari, J.M., Porras, C. et al. Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer’s disease. Nature Genetics (2026). https://doi.org/10.1038/s41588-026-02716-6
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41588-026-02716-6
Keywords: Alzheimer’s disease, microglia, perivascular macrophages, GPNMB, MITF, TREM2, APOE, SORL1, neuroinflammation, single-cell transcriptomics, aging, phagocytosis
Tags: aging-related changes in microgliaAlzheimer’s diseasehuman brain immune cellsimmune cell mapping in neurodegenerative diseasesimmune response in Alzheimer’s diseasemicroglia and brain tissue damagemicroglial activationmyeloid cell diversity in Alzheimer’sneuroinflammation in agingperivascular macrophages in neurodegenerationrole of microglia in synapse losssingle-cell sequencing of brain immune cells
