Timing-Dependent Effects of Estrogen Therapy on Alzheimer’s Disease Risk in Postmenopausal Women: A Comprehensive Meta-Analysis

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Traditional Abstracts 

FNU Vaibhav, MBBS  
Pt. B.D. Sharma PGIMS
Rohtak, India

Aditya Duhan, MD  
Suny Upstate Medical University
Syracuse, NY

Vipul Kaliraman, MBBS  
Maulana Azad Medical College
New Delhi, India

Seema Shahi, MD  
University of Louisville
Louisville, KY

FNU Vaibhav, MBBS  
N/A
Rohtak, India

Alzheimer's disease (AD) disproportionately affects postmenopausal women, with the decline in estrogen hypothesized to contribute to increased risk. While early observational studies suggested that estrogen therapy may reduce AD incidence by up to 30–45%, large randomized controlled trials (RCTs) in older women have shown conflicting results, with some indicating increased dementia risk. This meta-analysis evaluates the effect of various estrogen therapies, including 17β-estradiol, conjugated equine estrogen, and differing routes (oral vs. transdermal), on AD risk and progression.

Our findings underscore a dichotomy: estrogen therapy initiated near menopause may be neuroprotective, whereas late-life initiation increases dementia risk. These results highlight the need for tailored hormone strategies and further RCTs targeting early postmenopausal women before recommending estrogen therapy for AD prevention.

We conducted a comprehensive literature search (PubMed, Embase, Web of Science, Cochrane Library) through December 2024, following PRISMA guidelines. Both RCTs and observational studies comparing estrogen therapy to placebo or no treatment in postmenopausal women were included. Outcomes assessed were AD incidence, conversion of mild cognitive impairment (MCI) to AD, cognitive decline (using MMSE, ADAS-Cog, etc.), and biomarker/neuroimaging changes. Data were extracted independently by two reviewers, and pooled risk estimates were calculated using random-effects models. Subgroup analyses evaluated the impact of therapy type, route, timing of initiation (early [within 5 years of menopause] versus late), and study design.

RCTs in predominantly older women (≥65 years) revealed a significant 38% increased risk of dementia with estrogen therapy (RR 1.38, 95% CI 1.16–1.64), particularly with combined estrogen-progestin regimens. In contrast, observational studies, often including midlife initiators, indicated a 22% reduction in AD incidence (RR 0.78, 95% CI 0.64–0.95), with early initiation conferring up to a 32% lower risk. Cognitive outcomes and biomarker data were heterogeneous, though emerging evidence suggests timing critically modulates estrogen's neuroprotective effects.

Behavioral Neurology and Dementia

Neurodegeneration and Cell Death