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A study conducted by Weill Cornell Medicine researchers reveals that two key genetic mutations associated with Alzheimer’s disease (AD)—APOE4 and TREM2—combine to trigger damaging inflammation in the brain’s immune cells, specifically in females. Published in Neuron on September 30, 2024, the study highlights the importance of factoring in gender differences when researching Alzheimer’s and developing potential treatments.
Alzheimer’s disease disproportionately affects women, with almost twice as many women diagnosed compared to men. APOE4, a well-established genetic risk factor for Alzheimer’s, has been shown to increase risk more significantly in females. The new study adds to this understanding by showing how APOE4 interacts with a variant of the TREM2 gene (R47H) to cause more severe brain damage in female mice. These female mice exhibited greater buildup of tau proteins—known to be involved in cognitive decline—than males. These findings provide valuable insights into the mechanisms driving women’s heightened susceptibility to Alzheimer’s.
The study sheds light on how Alzheimer’s may develop differently between the sexes, particularly in individuals with genetic predispositions. Researchers found that in females carrying both APOE4 and TREM2 R47H, the brain’s immune cells—microglia—became dysfunctional with age, losing their ability to protect the brain. Instead of clearing away damaged cells and protein aggregates, the microglia started to produce inflammatory molecules through the cGAS-STING pathway. Importantly, by inhibiting this pathway, researchers were able to reduce inflammation and restore the microglia’s function. This discovery highlights a new potential target for therapies that could better address the unique ways in which Alzheimer’s affects women.
The study emphasizes the necessity of developing treatments that account for gender differences in Alzheimer’s disease progression. As researchers continue to unravel how high-risk genetic variants impact the immune system in females, they hope to pave the way for more personalized treatment options, which could improve outcomes for women facing this devastating disease.