Menopausal hormone therapy initiation around menopause linked to increased Alzheimer's risk

Abstract Objective To examine whether menopausal women who initiate systemic menopausal hormone therapy (MHT) around menopause (45-60 years old) have a different risk of developing dementia than those not taking MHT. Design Systematic review and meta-analysis of randomised controlled trials and longitudinal observational studies. Risk of bias was assessed using ROB-2 and ROBINS I-V2. Data sources MEDLINE, Web of Science, EMBASE, and Cochrane Library to 27 March 2026. Eligibility criteria for selecting studies Studies which measured dementia or cognitive decline in women who initiated systemic MHT between ages 45-60 or within 5 years of menopause, compared with placebo or no MHT. Authors contacted for additional details if needed. Main outcome measures Dementia, Alzheimers disease (AD), cognitive decline. Results 10 studies totalling 213,678 participants (189,525 in studies with the primary population). There was no significant increased risk in women with a uterus for all cause dementia (pooled hazard ratio (HR): 1.12; 95% CI 0.91-1.31, N=78,613, I2 = 96.9%), but increased AD risk (HR: 1.14; 95% CI 1.02, 1.29, N=134,865, I2 = 35.6%). Results were similar in sensitivity analyses including women with or without a uterus. Results for cognitive decline were variable. Conclusions MHT initiated around the age of menopause should not be prescribed for cognition or dementia prevention. It is not protective against dementia and may increase risk slightly. The magnitude of risk was similar in AD and dementia, but the latter with larger confidence intervals. Studies which followed up individuals rather than on health records lost people to follow up. This may account for difference in cognitive decline outcomes between studies, as people with cognitive impairment and dementia are more likely not to attend. MHT prescribing should balance benefits against risks, including evidence of a small increased dementia risk. There are few high-quality studies, so further research would inform recommendations. Key words Menopausal hormone therapy; dementia; cognitive decline Systematic review registration Prospero CRD420251010663 What is already known on this topic? 1. Menopausal hormone therapy (MHT) is effective for alleviating vasomotor symptoms. Contemporary guidelines recommend treatment should be initiated for such symptoms under age 60 and or within 10 years of menopause onset. 2. A large randomised trial on the topic found increased risk of dementia in women initiating MHT after the age of 65. 3. It is unknown whether initiating MHT around the age of menopause impacts the risk of dementia or cognitive decline. What this study adds 1. There was no evidence that taking MHT around the time of menopause decreases the risk of dementia or cognitive impairment. 2. They should not be prescribed for these indications. 3. We were able to find more studies which examine this question by contacting authors for additional data. 4. Initiating MHT in women with a uterus around the age of menopause increased the risk of Alzheimers disease slightly, by over 10%, and there is a similar but not significant effect in the fewer studies of all cause dementia. Women with or without a uterus show similar results. 5. We found no significant difference shown in cognitive decline, possibly due to loss to follow up. This may be because most studies of cognitive decline follow up cohorts and more of those with decline do not attend. In contrast, dementia and Alzheimers disease were measured using health records. 6. The increased risk of dementia is small but adds to information to help women decide whether they wish to take MHT for other symptoms.