APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function

Postmenopausal females who carry an APOEε4 allele are at higher risk of late-onset Alzheimer's Disease compared to age-matched APOEε4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function.

Young female homozygous APOEε3 and APOEε4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17β-estradiol, or left intact.

In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17β-estradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-estradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-estradiol in the APOEε4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOEε4 mice compared with APOEε3 mice. 17β-estradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17β-estradiol treatment was associated with lower cerebral artery stiffness in APOEε4 but not APOEε3 mice.

Overall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17β-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOEε3 mice but not in APOEε4 mice. The results suggest that 17β-estradiol supplementation has more cerebrovascular benefit for APOEε4 non-carriers.

What is known?: Females have twice the risk of Alzheimer's disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimer's disease compared with the APOE3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. What new information does this article contribute?: Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.