Clinically, Alzheimer's Disease (AD) presents with cognitive dysfunction, cell death, and amyloid-beta (AB) plaque and neurofibrillary tangle (NFT) formation. Moreover, age and gender are primary risk factors; women are at much higher risk for developing AD compared to men. Estrogens may be neuroprotective; however, clinical use in hormone replacement therapy (HRT) is controversial due to potential adverse effects. Experiments were conducted using the APPswe/PS1dE9 (DTG) and APPswe/PS1M146V/TauP301L (3xTgAD) transgenic mouse models to assess the efficacy of an estrogen pro-drug, estradiol-quinol (E2Q). Treatment groups consisted of vehicle, estradiol (E2), or E2Q in intact and ovariectomized (OVX) DTG females, intact DTG males, and intact 3xTgAD females and males. The objectives of this study were to 1) characterize AD progression in a double transgenic (DTG) murine model and compare the efficacy of treatment with estradiol (E2) or E2Q in ovariectomized (OVX) and intact females, 2) compare the effects of E2Q in males, 3) determine if E2Q affects neurodegenerative disease progression in the triple transgenic (3xTgAD) murine model in both males and females, and 4) assess the effects of the neurodegenerative disease progression on mitochondrial function and determine if E2Q affects these endpoints. E2Q did not stimulate uterine tissue and proved to be an effective intervention; treated DTG mice had better cognitive behavior, decreased amyloid precursor protein (APP), and amyloid beta (AB) protein levels. Taken together, these data suggest that E2Q has potential as a therapeutic for AD patients.