Hormone replacement therapy and dementia risk among postmenopausal women: evidence from the UK Biobank

ImportanceThe relationship between HRT use and dementia risk is unclear, with studies reporting both increased and decreased risk. ObjectiveTo identify modulators of the association between HRT use and dementia risk and identify potentially responsive subgroups of women. Design, setting, and participantsThis study used data from the UK Biobank, with baseline assessment conducted between 2006 and 2010 and follow up through to October 2022. The cohort included post-menopausal women without a diagnosis of dementia at baseline. ExposuresThe primary exposure was HRT use for a minimum duration of one year. Main outcomes and measuresMultivariable Cox proportional hazards regression models were employed to evaluate the relationship between HRT use and incident all-cause dementia, Alzheimers disease (AD) and non-AD dementia. Stratified analyses were conducted to explore heterogeneity in the associations and the impact of potential effect modifiers, including type of menopause (surgical vs. natural), cumulative lifetime exposure to natural estrogen and APOE {varepsilon}4 genotype. The association between age at HRT initiation and dementia risk was also examined. ResultsAmong 183,450 postmenopausal women (mean [SD] age at baseline, 60.3 [5.8] years), there were 3,948 dementia cases over 2,433,320 person-years of follow-up. Of these, 1,993 (50.5%) were classified as AD and 1,955 (49.5%) as non-AD dementia. HRT use was associated with lower risk of all-cause dementia (hazard ratio [HR], 0.90; 95% CI, 0.84-0.96). Stronger associations were observed in women with surgical menopause (HR 0.76; 95% CI, 0.67-0.85), APOE {varepsilon}4 carriers (HR 0.87; 95% CI, 0.80-0.95), and those with a lower lifetime exposure to natural estrogen (HR 0.78; 95% CI, 0.70-0.86). Initiation of HRT between 46 and 56 years was associated with reduced dementia risk. Conclusions and relevanceIn this large UK Biobank cohort, HRT use was associated with reduced risk of dementia among post-menopausal women. The association varied by age of initiation of HRT, APOE genotype, type of menopause, and endogenous lifetime estrogen exposure, highlighting the importance of personalised approaches to HRT prescribing. While further research is required to establish causality, the findings offer a foundation for tailored interventions aimed at mitigating lifetime dementia risk in women. Key PointsO_ST_ABSQuestionC_ST_ABSIs hormone replacement therapy (HRT) use associated with dementia risk in women? FindingsIn this prospective cohort study involving 183 450 post-menopausal women, HRT use for one year or more was associated with a reduced dementia risk. The risk reductions were more pronounced for women who had surgical menopause, had a shorter lifetime exposure to natural estrogen, or have at least one APOE {varepsilon}4 allele. Notably the protective associations were most evident in those who initiated HRT between 46 and 56 years. MeaningHRT use was associated with an overall reduction in dementia risk. The likelihood of benefit is nuanced and dependant on several common variables, highlighting the importance of a more personalised approach to HRT prescribing.