17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice

The study used middle-aged female mice expressing human APOE4 to test 17aE2, a weak estrogen previously shown to extend lifespan primarily in male mice. The authors found that 17aE2 conferred only limited improvements in aging phenotypes, indicating that the benefits seen in males may not fully translate to females carrying the APOE4 risk allele. These results align with earlier work showing that APOE genotype modulates 17aE2's healthspan benefits. The findings underscore the need for sex- and genotype-specific evaluation of potential Alzheimer's interventions and suggest that 17aE2 is unlikely to be a broadly effective therapeutic for APOE4 carriers.