New Horizons in Menopause, Menopausal Hormone Therapy, and Alzheimer’s Disease: Current Insights and Future Directions

Abstract Accumulating evidence suggests that the effects of menopausal hormone therapy (MHT) on risk of Alzheimer’s disease (AD) and all-cause dementia are influenced by timing of initiation relative to age and time-since-menopause and the type of formulation. Randomized clinical trials (RCTs) of MHT conducted in older postmenopausal women indicate an increased risk of dementia. While RCTs conducted in midlife are lacking, observational research has provided evidence for associations between midlife estrogen-only therapy (ET) use and a reduced risk of AD dementia, whereas estrogen-progestogen therapy (EPT) is associated with more variable outcomes. However, existing studies are heterogenous, and conventional endpoints might not adequately assess MHT’s potential for AD prevention. Herein, several approaches are being discussed, and the case is being made for utilizing AD biomarkers for assessment of early, AD-specific outcomes in relation to MHT use. From a clinical standpoint, findings that MHT may lower dementia risk warrant consideration as existing therapies like acetylcholinesterase inhibitors and memantine lack preventative efficacy, and vaccines for primary or secondary prevention are not yet available. MHT-associated risks, including breast cancer, stroke and venous thromboembolism, are generally considered rare (<10 events/10,000 women). Overall, the literature supports renewed interest in evaluating MHT as a sex-specific, time-sensitive approach for AD risk reduction, which is key to applying cumulated data in clinical decision making concerning AD prevention.