UK Biobank Cohort Links HRT to 16% Lower Alzheimer's Risk, Strongest in Surgical Menopause

Researchers tracked health records and identified nearly 4,000 dementia cases while adjusting for age, socioeconomic status, comorbidities, and medication use. Overall dementia risk fell 10% among users; Alzheimer's risk dropped 16%. Reductions reached 26% for surgical menopause and 16% for women with late menarche or early natural menopause. APOE4 carriers showed amplified associations, consistent with prior evidence that estrogen loss interacts with this genotype. The findings align with the critical-window hypothesis, as initiation between ages 46 and 56 produced the largest risk reductions. Earlier randomized data such as the Women's Health Initiative had raised safety concerns, yet this large cohort highlights subgroup benefits that may have been masked in broader trials. Healthy-user bias and residual confounding cannot be excluded in this design. Next steps require randomized trials stratified by menopause type, genotype, and HRT formulation, plus mechanistic studies of brain metabolism. Without such data, guidelines should continue to weigh individual risk profiles rather than adopt broad preventive recommendations.