Association of earlier age at menopause with risk of incident dementia, brain structural indices and the potential mediators: a prospective community-based cohort study

BACKGROUND: To date, there is no homogeneous evidence of whether earlier age at menopause is associated with incident dementia. In addition, the underlying mechanism and driven mediators are largely unknown. We aimed to fill these knowledge gaps. METHODS: This community-based cohort study included 154,549 postmenopausal women without dementia at enrolment (between 2006 and 2010) from the UK Biobank who were followed up until June 2021. We followed up until June 2021. Age at menopause was entered as a categorical variable (<40, 40–49, and ≥50 years) with ≥50 years taken as a reference. The primary outcome was all-cause dementia in a time-to-event analysis and the secondary outcomes included Alzheimer's disease, vascular dementia, and other types of dementia. In addition, we investigated the association between magnetic resonance (MR) brain structure indices with earlier menopause, and explored the potential underlying driven mediators on the relationship between earlier menopause and dementia. FINDINGS: 2266 (1.47%) dementia cases were observed over a median follow-up period of 12.3 years. After adjusting for confounders, women with earlier menopause showed a higher risk of all-cause dementia compared with those ≥50 years (adjusted-HRs [95% CIs]: 1.21 [1.09–1.34] and 1.71 [1.38–2.11] in the 40–49 years and <40 years groups, respectively; P for trend <0.001). No significant interactions between earlier menopause and polygenic risk score, cardiometabolic factors, type of menopause, or hormone-replacement therapy strata were found. Earlier menopause was negatively associated with brain MR global and regional grey matter indices, and positively associated with white matter hyperintensity. The relationship between earlier menopause and dementia was partially mediated by menopause-related comorbidities including sleep disturbance, mental health disorder, frailty, chronic pain, and metabolic syndrome, with the proportion (95% CI) of mediation effect being 3.35% (2.18–5.40), 1.38% (1.05–3.20), 5.23% (3.12–7.83), 3.64% (2.88–5.62) and 3.01% (2.29–4.40), respectively. Multiple mediator analysis showed a combined effect being 13.21% (11.11–18.20). INTERPRETATION: Earlier age at menopause was associated with risk of incident dementia and deteriorating brain health. Further studies are warranted to clarify the underlying mechanisms by which earlier age at menopause is linked to an increased risk of dementia, and to determine public health strategies to attenuate this association. FUNDING: 10.13039/501100001809National Natural Science Foundation of China, the Science and Technology Program of Guangzhou, the 10.13039/501100015956Key Area Research and Development Program of Guangdong Province, the 10.13039/501100002858China Postdoctoral Science Foundation, and the 10.13039/501100021171Guangdong Basic and Applied Basic Research Foundation.