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 compound, estrogen monotherapy versus 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. Key points:• The influence of hormone therapy (HT) on cognition in postmenopausal women with Alzheimer's disease (AD) is inconclusive mainly due to a translational gap based on inadequate animal models, clinical inter-/intra-group heterogeneity and often incomparable HT study design.• Cognitive outcomes in clinical trials are mostly influenced by HT composition, its dose, timing and route of administration, as well as by ApoE carrier status, co-morbidity and concomitant therapy.•Design of estrogen/progesterone modulators that would optimize cognitive benefits and tailored HT may lead to more successful prevention and treatment of AD in postmenopausal women.