Associations of oral contraceptives and hormone replacement therapy with incident dementia risk: a population-based cohort study

The relationships between exogenous hormones and dementia, as well as cognitive function in females, remains debated. This study aimed to investigate the associations of exogenous hormone exposure (oral contraceptives [OC] and hormone replacement therapy [HRT]) with incident dementia risk, cognitive function and changes in brain structures. Multivariate Cox proportional hazard regression models were used to assess the associations between exogenous hormone exposure and dementia incidence. Linear regression models were employed to explore the relationships of exogenous hormone exposure and cognitive performances. Mediation models were conducted to explore the underlying mechanisms driven by brain structures. A total of 233,896 female participants from the UK Biobank were included. In fully adjusted models, OC use was associated with reduced risks of all-cause dementia (ACD) (HR [95% CI], 0.806 [0.724-0.897]), Alzheimer's disease (AD) (HR [95%CI], 0.767 [0.659-0.893]) and vascular dementia (VaD) (HR [95%CI], 0.735 [0.578-0.934]). HRT was associated with decreased risks of ACD (HR [95%CI], 0.897 [0.811-0.992]) and AD (HR [95%CI], 0.804 [0.696-0.928]). Duration of OC use showed a non-linear (J-shaped) association with the risks of ACD and AD. In addition, brain structures, including the bilateral pallidum and left thalamus proper were identified as potential mediators in the relationships between the duration of OC use and cognitive performance. To summarize, exogenous hormone use is associated with reduced dementia risk and better cognitive function, with pallidum and thalamus possibly mediating the associations.