Translational potential of JAX humanized‐APOE mice model: Accelerated midlife endocrine aging in hAPOEε4/4 females

Abstract

AbstractBackgroundAge, female sex and APOEε4 genotype are the greatest Alzheimer’s (AD) risk factors, with a stronger APOEε4 link to AD in women. The APOE‐sex interaction is also evident in hAPOE mouse models where APOEε4 induces more severe neurodegeneration and cognitive deficits in female mice. However, the mechanisms by which these two risk factors converge to disrupt brain function remain elusive.MethodTo investigate effect of APOE genotype on midlife endocrine aging, 6‐, 9‐ and 15‐month hAPOEε3/3 and hAPOEε4/4 female mice were stratified into 3 different endocrine aging groups based on vaginal cytology profiles: regular cyclers (consistent 4–5 day cycles), irregular cyclers (of 6–9 day cycles), and acyclic (no cycling >9 days). Plasma levels of metabolomic makers were measured. Brain mitochondrial function was quantified.ResulthAPOEε4/4 females exhibited accelerated endocrine aging evidenced by increased magnitude of brain metabolic defect coupled with inability to mount an adaptive bioenergetic response. Systems biology of endocrine aging initially identified in perimenopausal rat model were replicated in the hAPOEε3/3 mouse model. In contrast, hAPOEε4/4 females exhibited accumulation of adipose tissue with high plasma triglyceride and accelerated ketone body dysregulation during perimenopausal transition, indicating deficits in adaptive metabolic response required for sustaining brain metabolic demand during aging. Further, hAPOEε4/4 females exhibited greater perimenopause‐ and menopause‐induced brain mitochondrial dysfunction.ConclusionOutcomes of these analyses provide a plausible mechanistic pathway underlying the greater risk of AD in APOEε4 females. Further, these data indicate that the bioenergetic crisis underlying metabolic reprogramming in brain are greater in the APOEε4 female brain while compensatory adaptive responses are compromised. These findings provide a rational mechanistic precision medicine approach to intervene during midlife to prevent or delay the onset of the prodromal / preclinical stage of AD.This work was supported by NIA grants P01‐AG026572 Project 2 to RDB and Animal Core to TW.