This prospective cohort study used UK Biobank data (n=183,450 postmenopausal women; mean follow-up 13.3 years) to evaluate whether HRT use (≥1 year) reduces all-cause dementia, Alzheimer's disease (AD), and non-AD dementia risk, and to identify which subgroups benefit most based on menopause type, APOE ε4 status, lifetime estrogen exposure, and age at HRT initiation.
Over 2.43 million person-years, 3,948 dementia cases arose. HRT was linked to lower all-cause dementia (HR 0.90; 95% CI 0.84–0.96) and AD (HR 0.84; 95% CI 0.77–0.92), but not non-AD. Benefit was strongest in surgical menopause (HR 0.74; 95% CI 0.65–0.84), APOE ε4 carriers (HR 0.87; 95% CI 0.80–0.95), and women with shorter lifetime estrogen exposure (<37 years; HR 0.84; 95% CI 0.77–0.93). HRT started at ages 51–56 showed the greatest risk reduction (HR 0.77; 95% CI 0.70–0.86); initiation after age 56 was not protective.
- Observational design with healthy-user bias; residual confounding cannot be excluded despite multivariable adjustment. - No data on HRT formulation (estrogen-only vs. combined), dose, or route of administration—a key gap given that estrogen-only and combined HRT have different risk profiles. - Dementia ascertainment relies mainly on secondary care hospital records, likely missing milder cases; cohort skews White and socioeconomically advantaged, limiting generalizability.
For women at higher dementia risk—especially those with surgical menopause, APOE ε4 status, or shorter reproductive span—HRT initiated in the perimenopausal window (roughly ages 46–56) may offer the greatest cognitive benefit. Clinicians should weigh these subgroup-specific signals when counseling women about HRT, while awaiting confirmatory RCT data.
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