Age-related endocrine dyscrasia has been postulated as the etiological event driving age-related neurodegeneration in Alzheimer’s disease (AD). Alterations in endocrine signaling with menopause and andropause, involving luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH) and sex steroids, have been proposed to drive the re-entry of post-mitotic neurons into an abortive cell cycle that leads to cell dysfunction, cell death and alterations in the blood-brain barrier. The cell cycle regulatory properties of LH, and its fetal homolog, human chorionic gonadotropin (hCG), have been well demonstrated in both pluripotent human and totipotent murine embryonic stem cells, and in the hippocampus of the adult mouse. Importantly, dysregulation of LH signaling drives a number of cell cycle-related events associated with neurodegeneration. This includes LH induction of amyloid-b precursor protein processing for the generation of mitogenic Ab, and the activation of key kinases that regulate cell cycle progression and tau phosphorylation. A number of complimentary cognitive studies demonstrate the negative consequences of a high circulating LH:sex steroid ratio on rodent cognitive performance. These preclinical observations are supported by 2 large retrospective epidemiological studies demonstrating that the suppression of circulating gonadotropins (decreased gonadotropin:sex steroid ratio) with Lupron Depot® (leuprolide acetate) dramatically reduced the incidence of AD. Moreover, a Phase II, double-blind, placebo-controlled, dose-ranging study conducted in 109 women aged 65 years or older with mild to moderate AD found that cognitive function was preserved over 48 weeks in those patients taking high-dose Lupron Depot® and an acetylcholine esterase inhibitor (AChEI). Together, these data strongly support endocrine dyscrasia and the subsequent loss of cell cycle control as a primary etiological event in the development of AD. Appropriate therapeutic strategies targeting hypothalamic-pituitary-gonadal axis homeostasis are suggested to offset and delay the onset of neurodegeneration and cognitive decline. As such, the positive interaction between Lupron and AChEI’s warrants further investigation..