Introduction: Women are at a greater risk of developing Alzheimer’s disease (AD) compared to men. This difference has one of its causal explanations in the association with sex hormone levels and their abrupt decline during menopause. Objectives: Review how postmenopausal sex hormone changes influence AD and how hormonal therapy (HT) may impact this trajectory, providing an overview of the literature.

Methods: A systematic review, Prospero-ID 654328, was conducted by searching bibliographic databases, including PubMed, Scopus, Embase, Web of Science, and VHL, using the Mesh terms “women,” “Alzheimer’s,” “sex hormones,” and “menopause”. The inclusion criteria followed the PICO (population - postmenopausal women, intervention - HT and hormone levels, control - women without AD, and outcomes - cognitive outcome) strategy and the quality of nonrandomized studies, as case control and cohort, were assessed using the Newcastle-Ottawa Scale. The articles were blinded-of and reviewed by tree reviewers. Out of the 263 articles identified, 19 met all the PRISMA criteria, and were included.

Results: The reviewed studies consistently demonstrate that the decline in sex hormones, particularly estradiol, plays a significant role in the potential development of AD in postmenopausal women. An earlier onset of menopause is associated with reduced grey matter volume in key brain regions, such as the hippocampus, parahippocampal gyri, perirhinal cortex, and amygdala, all crucial for memory. These structural changes suggest that an earlier age at menopause may contribute to an increased risk of AD, whereas a longer reproductive span may serve as a protective factor. Although HT does not appear to significantly alter the overall relationship between menopause and AD incidence, two studies indicate that HT, particularly 17β-estradiol, may provide cognitive protection, including reduced β-amyloid deposition, in women at higher genetic risk, such as those with the APOE ε-4 allele or a family history of AD. Furthermore, studies suggest that surgical menopause, particularly due to early ovarian removal, increases the risk of AD in women. Sleep disturbances associated with this early menopause may act as a significant contributing factor, potentially accelerating the onset of the disease.

Conclusion: The evidence suggests that the decline of sex hormones, particularly estradiol, shows a higher risk of developing AD among postmenopausal women. The observed reduction of grey matter in key memory-related brain regions highlight the impact of early menopause. Moreover, HT does not significantly alter the general relationship between menopause and AD incidence, but findings suggest that a specific treatment with 17β-estradiol may confer cognitive benefits for high risk patients, with the APOE ε-4 allele or a family history of the disease. Additionally, surgical menopause, with oophorectomy procedure, which increases the risk of sleep disturbance problems, is linked to a higher risk of AD.