Vulnerability to
Alzheimer's disease (AD) is increased by several risk factors, including midlife
obesity, female sex, and the depletion of
estrogens in women as a consequence of menopause. Conversely,
estrogen-based
hormone therapies have been linked with protection from age-related increases in adiposity and
dementia risk, although treatment efficacy appears to be affected by the age of initiation. Potential interactions between
obesity, AD, aging, and
estrogen treatment are likely to have significant impact on optimizing the use of
hormone therapies in postmenopausal women. In the current study, we compared how treatment with the primary
estrogen, 17β-estradiol (E2), affects levels of AD-like neuropathology, behavioral impairment, and other neural and systemic effects of preexisting diet-induced
obesity in female 3xTg-AD mice. Importantly, experiments were conducted at chronological ages associated with both the early and late stages of reproductive senescence. We observed that E2 treatment was generally associated with significantly improved metabolic outcomes, including reductions in
body weight, adiposity, and
leptin, across both age groups. Conversely, neural benefits of E2 in obese mice, including decreased β-
amyloid burden, improved behavioral performance, and reduced microglial activation, were observed only in the early aging group. These results are consistent with the perspective that neural benefits of
estrogen-based
therapies require initiation of treatment during early rather than later phases of reproductive aging. Further, the discordance between E2 protection against systemic versus neural effects of
obesity across age groups suggests that pathways other than general metabolic function, perhaps including reduced microglial activation, contribute to the mechanism(s) of the observed E2 actions. These findings reinforce the potential systemic and neural benefits of
estrogen therapies against
obesity, while also highlighting the critical role of aging as a mediator of
estrogens' protective actions.