Jorge Alejandro Arias-Vega
1. - Harvard T.H. Chan School of Public Health, ECPE–PPCR Program, Boston, MA, USA, 2. - Universidad Nacional Autónoma de México, Facultad de Medicina, Ciudad de México, México
Marcelo Henrique Lima Silvestre
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 3.- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil
María Fernanda Morales-Labarca
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA 4.- Essity Medical & Health, Chile
Gerardo Mordojovich Ruiz
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 5.- Unidad de Cirugía de tórax, Clínica Alemana de Santiago, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
Raquel María Vera Rodríguez
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 21.- Hospital Universitario "Dr. José Eleuterio González, Monterrey, México
Pamella Paul
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA
Alberto Prat Barrueto
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 6.- Centro Avanzado de Epilepsia, Clínica Alemana de Santiago, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
Alicia Shoji
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 7.- Faculty of Veterinary Medicine and Animal Science Universidade Estadual de São Paulo, São Paulo, Brasil
Valeria Mayorga Mata
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 8.- Universidad Francisco Marroquín, Guatemala, Guatemala
Leticia Rielo de Moura Santos
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 9.- Centre Integré de Santé et des Services Sociaux de la Gaspésie, Québec, Canada
Bruno Cateb Resende de Oiliveira
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 10.- Faculdade São Leopoldo Mandic - Campinas, Campinas, Brasil.
Feras Alsalem
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 11.- Klinikum Chemnitz, Chemnitz, Germany
Andrei-Antonio Michael Caracioni
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA 12.- Department of Cardiac Surgery, Medical University of Graz, Austria
Miriam Barreto Baie
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA., 13.- Instituto de Medicina Integral Professor Fernando Figueira (IMIP), Recife-PE, Brasil
Iselle Suero Matos
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 14.- Instituto Tecnológico de Santo Domingo, Santo Domingo, República Dominicana
Shirley Olivia Arias Hernández
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 15.- Universidad Peruana Cayetano Heredia, Lima, Perú
Daniel Agustín Vásquez Quispe
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 19.- IBCC Oncologia - Instituto Brasileiro de Controle do Câncer
Anaisabel Garza
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA 8.- Universidad Francisco Marroquín, Guatemala, Guatemala
Arisa Chindahporn
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 16.- Thammasat University, Pathum Thani, Thailand
Rafael Cotorreal Javier
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 17.- CEDIMAT, Santo Domingo, República Dominicana
Ana Perales
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 10.- Faculdade São Leopoldo Mandic - Campinas, Campinas, Brasil.
Fernanda Leiko Yamashita
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 10.- Faculdade São Leopoldo Mandic - Campinas, Campinas, Brasil.
Francisco Osvaldo García Pérez
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 18.- Instituto Nacional de Cancerología, Ciudad de México, México.
Francisco Valenzuela Flores
1.- Harvard T.H. Chan School of Public Health, ECPE - PPCR Program., Boston, MA, USA, 20.- Clínica Dávila, Santiago, Chile
Abstract
Background: Dementia is a highly prevalent condition with a known predominance in women. Estrogens are hypothesized
to exert neuroprotective effects, raising interest in whether menopausal estrogen decline contributes to dementia risk.
Consequently, hormone replacement therapy (HRT) has been widely investigated as a potential protective or risk-modifying
intervention; however, existing evidence remains conflicting. This systematic review and meta-analysis aimed to evaluate
the association between HRT use and the risk of dementia and to explore sources of heterogeneity across studies.
Methods: A systematic search of MEDLINE (PubMed) and Scopus was conducted for studies published between January
1990 and May 2025. Randomized controlled trials (RCTs), cohort studies, and case–control studies evaluating estrogenreplacement therapy (ERT) or combined hormone therapy (CHT) in postmenopausal women aged >45 years, with outcomes of all-cause dementia or Alzheimer’s disease (AD), were included. Only human studies published in English, German,
Portuguese, French, or Spanish were eligible. After screening 5,283 records, 32 studies met the inclusion criteria. Data were
qualitatively synthesized, and random-effects meta-analyses were performed, with prespecified subgroup and sensitivity
analyses.
Results: Thirty-two studies (2 RCTs, 17 cohort studies, and 13 case–control studies) published between 1996 and 2024
were included, with sample sizes ranging from fewer than 200 to over 100,000 participants and follow-up durations from
2 to more than 20 years. In unadjusted analyses, HRT use showed a borderline statistically significant association with
lower dementia risk (OR 0.83; 95% CI 0.70–0.99); however, results were highly heterogeneous. In subgroup analyses,
estrogen-replacement therapy (ERT) demonstrated a non-significant trend toward reduced dementia risk (OR 0.77; 95%
CI 0.59–1.01), whereas no protective association was observed for combined hormone therapy (CHT). Interestingly, effect
estimates differed by study design, with observational studies resulting in lower risk and randomized controlled trials
indicating increased risk.
Conclusion: The available evidence does not support the use of HRT for the prevention of dementia. Observed associations
are highly heterogeneous and appear strongly influenced by methodological factors, hormone regimens, and study design.
Future research should prioritize well-designed studies with adequate follow-up, standardized diagnostic criteria, and
careful consideration of timing, formulation, and confounding variables to better clarify the relationship between HRT and
dementia risk.
