A gene tied to a very high risk of Alzheimer’s disease triggers immune cells in the brain to keep inflammation alive, a finding from the Gladstone Institute reported in Cell Stem Cell. The APOE4 variant is the strongest genetic risk factor for late onset Alzheimer’s, and the study shows how it can push brain immune cells toward damaging activity.
In a pivotal experiment, scientists introduced human brain cells that produce the APOE4 protein into mice. This molecule is known to raise the risk of developing Alzheimer’s, yet the exact mechanism has remained elusive.
To test the role of immune cells called microglia, researchers removed microglia from the animals’ brains. At the same time, the harmful effects driven by APOE4 diminished markedly. The results indicate that the interplay between APOE4 and microglia is a driving force behind Alzheimer’s disease.
In a healthy brain microglia help clear waste and misfolded proteins. But when APOE4 is present, these same cells switch to promoting inflammation and the accumulation of beta-amyloid and tau proteins.
The APOE4 variant may raise Alzheimer’s risk by about 12-fold, underscoring the potential number of people who could benefit from targeted interventions. The new study could form the groundwork for therapies aimed at preventing dementia in carriers of APOE4.
This research adds an important layer to the growing evidence that immune system activity plays a central role in Alzheimer’s disease and that modulating this activity may become a viable route for prevention. By focusing on microglia and their interaction with APOE4, scientists are charting a path toward treatments that address the root immune processes rather than just the downstream protein aggregates.
While the findings come from mouse models incorporating human APOE4, they offer a compelling model for how brain inflammation can be tied to genetic risk. Researchers caution that translating these results to people will require careful validation and clinical testing, but the direction is clear: targeting microglial responses could alter the trajectory of disease for many at risk due to APOE4.
Ongoing work will seek to determine whether similar mechanisms operate in humans and whether safe strategies can adjust microglial activity without compromising the brain’s defense systems. The study strengthens the case that inflammation is a real driver of neurodegeneration in susceptible individuals and adds to a growing toolkit of strategies aimed at delaying or preventing Alzheimer’s progression.