Hormone therapy (HT) is prescribed during or after menopausal transition to replace the decline in estrogen and progesterone levels. While some studies indicate that estrogen and progesterone depletion in postmenopausal women might carry a significant risk for developing sporadic Alzheimer's disease (sAD), which may be reduced by HT, recent clinical trials oppose this beneficial effect. This review points to possible reasons for these mixed data by considering the issues of both preclinical and clinical trials, in particular, the representativeness of animal models, timing of HT initiation, type of HT (different types of estrogen compounds, estrogen monotherapy vs. estrogen-progesterone combined therapy), mode of drug delivery (subcutaneous, transdermal, oral, or intramuscular), and hormone dosage used, as well as the heterogeneity of the postmenopausal population in clinical trials (particularly considering their sAD stage, anti-AD therapy, and hysterectomy status). Careful planning of future preclinical and clinical HT interventional studies might help to elucidate the effect of HT on cognitive status in postmenopausal women with sAD, which will eventually contribute to more effective sAD prevention and treatment.