A study published in Neuron reports on Mar. 29 that the APOE4 gene variant changes immune and lymphatic pathways in the brain differently for females and males, leading to opposite effects on cognition when innate immunity is suppressed.
This research matters because APOE4 is known to increase the risk of Alzheimer's disease, but its impact varies by sex. Understanding these differences could help develop targeted treatments for cognitive decline related to aging and neurodegenerative disorders.
Researchers found that while both male and female mice with two copies of APOE4 had similar numbers of innate immune cells, there were notable differences in inflammatory responses. Females showed more macrophages expressing MHC class II and CD206 regardless of genotype. When treated with a CSF1R inhibitor called PLX5622, both sexes experienced reduced macrophage frequencies, but gene expression changes were more pronounced in certain cell types depending on sex.
The study also observed that middle-aged male mice with two copies of APOE4 had longer lymphatic vessels but poorer cerebrospinal fluid drainage compared to females. Inflammatory markers were higher in female mice carrying APOE4 than their E3 counterparts, while males did not show such differences at this stage. Cognitive tests revealed that suppressing innate immunity worsened cognitive function in male mice but improved it in females carrying two copies of APOE4.
Analysis using human brain data confirmed distinct responses among different immune cell populations based on sex and presence of the E4 allele. The researchers say these findings highlight "that the meningeal dura could be a relevant neuroimmune niche in the context of aging-related neurodegenerative disorders, whose risk varies by sex, age, and E4 status." They add that understanding these mechanisms will be important for developing tailored immunotherapies for conditions like Alzheimer's disease.
