Alzheimer’s disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.
