A study found that when microglia, the brain's waste-clearing cells, become overly activated, the brain's defense system weakens and the risk of Alzheimer's disease can increase. The saying that even a good thing can be harmful if overdone has proven true in the brain.
A research team led by Professor Ana Griciuc at Harvard Medical School's Massachusetts General Hospital (MGH) said in Neuron on Oct. 17 (local time) that "if you keep the switch that activates microglia turned on, their waste-clearing and inflammation-regulating functions actually decline."
Microglia are immune cells that are a type of glial cell supporting neurons. They remove damaged or dead cells and fight pathogens. In particular, they remove aggregates of amyloid beta protein that cause Alzheimer's dementia.
TREM2 is a gene that produces a switch protein that activates or deactivates microglia. Under normal conditions, it keeps microglia on standby, then switches them to a disease-responsive state to clean up when protein debris accumulates. For this reason, it has been known that if TREM2 function weakens, the risk of developing Alzheimer's disease increases.
The research team overturned this conventional view. They said that when a T96K mutation makes the TREM2 gene "always on," microglial function actually declines and the likelihood of developing Alzheimer's disease increases.
First, the team analyzed human genetic data and identified a T96K gain-of-function variant that strengthens TREM2 activity in microglia beyond normal levels. Next, they observed how this genetic variant affects mice whose brains are in an Alzheimer's disease–like state.
The experiments showed that the T96K variant impaired the waste-clearing and immune functions of microglia. First, microglia failed to properly gather around protein debris. It is as if cleaners cannot get to the trash.
The T96K variant also reduced the amount of "soluble TREM2" secreted by microglia. Soluble TREM2 exchanges signals with surrounding cells and helps regulate immune responses. The T96K variant also interfered with signals microglia send out for clearing and inflammation control.
This study is the first to show that not only loss-of-function, in which a specific gene does not operate, but also gain-of-function mutations that operate excessively can be linked to Alzheimer's disease risk. The team noted that these results should prompt a reexamination of treatment strategies targeting the TREM2 gene. Because indiscriminately activating TREM2 could worsen the disease, future treatments should focus more on modulation.
The team said, "The fact that the impact of the T96K variant differs by sex could provide an important clue to understanding the mechanisms of Alzheimer's disease onset," adding, "We plan to determine how gain-of-function variants like T96K affect immune responses, lipid metabolism, and cellular aging in cells similar to human microglia and in experimental animals."
References
Neuron (2025), DOI: https://doi.org/10.1016/j.neuron.2025.09.032