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Basic Science and Pathogenesis.

Claudia Barth1

  • 1Diakonhjemmet Hospital, Oslo, Oslo, Norway.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
PubMed
Summary
This summary is machine-generated.

This study found no causal link between estradiol levels and Alzheimer's disease (AD) risk in females or males. Further research is needed to explore other factors influencing AD development.

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Area of Science:

  • Neuroscience
  • Genetics
  • Endocrinology

Background:

  • Alzheimer's disease (AD) is a sex-biased brain disorder with higher prevalence in females.
  • Estradiol, a potent estrogen, has been inconsistently linked to AD risk, with observational studies facing methodological limitations.
  • Mendelian randomization (MR) offers a genetic approach to investigate causal relationships, overcoming confounding and reverse causation.

Purpose of the Study:

  • To investigate the causal relationship between genetically predicted estradiol-related factors and Alzheimer's disease (AD) risk in females.
  • To utilize two-sample MR analyses to assess the impact of estradiol and lifetime estradiol exposure on AD.
  • To determine if genetic predisposition to estradiol levels influences AD susceptibility.

Main Methods:

  • Conducted two-sample MR analyses using female-specific GWAS data for estradiol levels and related factors (reproductive span, age at menarche/menopause, childbirths).
  • Employed inverse-variance weighted and robust estimation methods (MR-Egger, weighted median, etc.) for univariable MR.
  • Performed sensitivity analyses, including multivariable MR with BMI and replication in independent female and male samples.

Main Results:

  • Consistently found no significant associations between estradiol-related factors and AD risk across all female samples.
  • Results remained robust after sensitivity analyses, including multivariable MR and BMI adjustment.
  • Replication in independent female and male cohorts confirmed the lack of a significant causal link.

Conclusions:

  • The study does not support a causal role for estradiol-related factors in Alzheimer's disease risk in either females or males.
  • Future research should explore other influencing factors and employ sex-specific causal frameworks to understand hormonal effects on AD.
  • Investigating time-varying hormonal effects and periods of heightened susceptibility, such as perimenopause, is recommended.