Protection against APOE4-associated phenotypes with the longevity-promoting intervention 17α-estradiol in middle-aged male mice

The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Interventions that promote healthspan(definition) and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles. Beginning at age 10 months, male APOE3 or APOE4 mice were treated for 20 weeks with 17αE2 or vehicle then compared body-wide for indices of middle-aged phenotypes. Across peripheral and neural measures, APOE4 associates with poorer outcomes. Notably, 17αE2 treatment generally improves outcomes in a genotype-dependent manner, favoring APOE4 mice, including reductions in body weight, plasma leptin, hepatic steatosis, learning and memory, and oxidative damage in the brain. Plasma lipidomics and microglial transcriptomics show reductions in genotype-specific differences with 17αE2 treatment. These findings demonstrate that APOE4 promotes systemic and neural aging phenotypes linked to AD and that 17αE2-mediated healthspan actions show a positive APOE4 bias. Collectively, the findings suggest that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with the APOE4 genotype. People with a particular sequence in a part of their DNA called APOE (named APOE4) are more likely to have a reduced lifespan and have a higher risk of developing some age-related disorders, including Alzheimer’s disease. We tested whether a drug that extends lifespan and healthy aging in mice, called 17α-estradiol (17αE2), reduces the aging effects of APOE4. We compared male mice with different APOE sequences for 20 weeks during early middle age. As expected, we found that mice with the APOE4 sequence showed more signs of aging, but that 17αE2 improved several health-related measures, often with a bigger effect in mice with APOE4. These results suggest that treatments that promote healthy aging may be especially helpful for people with APOE4, potentially reducing their risk for age-related diseases such as Alzheimer’s disease. McGill et al. compare the effects of the longevity-promoting compound 17α-estradiol (17αE2) in male mice carrying the common human APOE3 allele versus the Alzheimer-associated APOE4 allele. Treatment with 17αE2 in early middle-age improves outcomes body-wide with greater benefits in APOE4 mice, suggesting genotype-specific healthspan effects.