Associations of age at menopause, bilateral oophorectomy, hysterectomy and hormone replacement therapy with glycaemia and risk of dementia: a study based on the population-based UK Biobank cohort

Introduction
Menopausal factors, including age at menopause, bilateral oophorectomy, hysterectomy and hormone replacement therapy (HRT), have been associated with dementia risk, which might be due to increased glucose levels after menopause. This study investigated the associations of these menopausal factors with glycaemia and dementia risk, and whether glycaemia mediates the association of menopausal factors with dementia risk.

Methods
We used longitudinal data from the population-based UK Biobank cohort (n=147 119 women; mean±SD age 55.2±8.0 years at baseline). Menopausal status, bilateral oophorectomy, hysterectomy, HRT and age at natural menopause, surgery and HRT were self-reported. Glycaemia was measured with fasting plasma glucose and haemoglobin A1c (HbA1c) levels. Dementia diagnoses were ascertained from hospital records. Cox proportional hazards regression analyses tested the associations between menopausal factors, glycaemia and dementia risk. Causal mediation models were used to test mediation.

Results
After a mean follow-up of 12.5±1.6 years, 1385 participants had incident dementia. Though there was a direct effect of bilateral oophorectomy, hysterectomy, lifetime HRT and age at natural menopause and surgery on fasting plasma glucose and HbA1c levels, only age at natural menopause (HR=0.97 (95% CI 0.96 to 0.99) per year and HR=1.31 (95% CI 1.08 to 1.60) for early natural menopause) and lifetime HRT in women with natural menopause (HR=1.13 (95% CI 1.00 to 1.27)) were associated with dementia risk. Causal mediation analyses showed that up to 4.7% of the total effect of age at natural menopause on dementia risk was mediated by HbA1c levels, while both fasting plasma glucose and HbA1c affected the increased dementia risk for lifetime HRT in women with natural menopause.

Conclusions
We observed associations between bilateral oophorectomy, hysterectomy, lifetime HRT and age at natural menopause and surgery with glycaemia. An earlier age at natural menopause was associated with increased dementia risk, and HbA1c marginally mediated this association. Inconsistent associations between HRT and dementia risk require further research.