A sex‐specific “hormone–bone–brain” axis in Alzheimer's disease: Integrating Global Burden of Disease data and Mendelian randomization analysis to reveal the causal role of osteocalcin

BACKGROUND Alzheimer's disease (AD) shows a significant sex disparity, with a higher incidence in women. Although reduced estradiol (E2) is a conventional explanation, inconsistent hormone‐replacement therapy outcomes suggest that other regulators, like the postmenopausal rise in follicle‐stimulating hormone (FSH), may be involved. The bone‐secreted hormone osteocalcin (OCN), normally neuroprotective, is paradoxically elevated in high‐risk postmenopausal women, implying a complex “hormone–bone–brain” axis. OBJECTIVE To systematically dissect the causal relationships between E2, FSH, OCN, and AD risk, providing a mechanistic explanation for the AD sex disparity. METHODS We integrated a macro‐epidemiological analysis (2021 Global Burden of Disease [GBD] data) to quantify the disparity and a robust two‐sample Mendelian randomization (MR) analysis (large‐scale genome‐wide association study [GWAS] data) to explore causal pathways. The primary MR method was inverse‐variance weighted (IVW), supported by comprehensive sensitivity analyses. RESULTS GBD data confirmed higher global AD prevalence and mortality in women, especially after age 55. MR analysis revealed a positive causal effect of genetically predicted OCN levels on AD risk (odds ratio [OR] = 1.116; 95% confidence interval [CI]: 1.015‐1.228; p = 0.024). No direct causal effect was found from E2 or FSH on AD. Crucially, mediation MR established that FSH causally increases OCN levels (OR = 1.080; p = 0.027), with OCN fully mediating FSH's effect on AD, establishing the novel “FSH → OCN → AD” pathway. Reverse MR ruled out reverse causation. CONCLUSION This study provides the first genetic evidence of a novel endocrine–bone–brain axis: “FSH → OCN → AD.” This suggests that postmenopausal FSH surges drive AD risk via OCN‐mediated pathology. OCN is thus a key causal mediator and promising biomarker/therapeutic target for AD intervention in women.