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Basic Science and Pathogenesis.

Danielle M Reid1,2, Noah Cook1,2, Chenyu Yang1,2

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Summary
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This study identified sex-specific genetic loci and genes associated with Alzheimer's disease (AD) risk using large-scale genome-wide association studies (GWAS) and proteome-wide association studies (PWAS). Findings highlight sex differences in AD pathogenesis and potential for personalized medicine.

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Area of Science:

  • Neurogenetics
  • Genomics
  • Alzheimer's Disease Research

Background:

  • Alzheimer's disease (AD) exhibits sex-specific differences in prevalence and progression.
  • Understanding these sex differences is crucial for developing effective treatments.

Purpose of the Study:

  • To conduct the largest sex-stratified genome-wide association study (GWAS) for AD.
  • To identify sex-specific, potentially druggable AD causal proteins using proteome-wide association studies (PWAS).
  • To integrate GWAS with proteogenomic data (protein quantitative trait loci [pQTL]) from brain and cerebrospinal fluid (CSF).

Main Methods:

  • Performed sex-stratified and sex-heterogeneity AD GWAS in European ancestry individuals across three stages.
  • Conducted PWAS by integrating sex-stratified AD GWAS with sex-matched and non-sex-stratified protein-specific variant weights.
  • Evaluated sex heterogeneity consistency using admixed African ancestry AD GWAS and PWAS.

Main Results:

  • GWAS identified 20 sex-specific AD loci (14 female, 5 male), with 65% showing consistent sex heterogeneity in African ancestry data.
  • Brain and CSF AD PWAS identified 66 and 19 genes associated with AD in females, and 23 and 17 in males, respectively.
  • Identified 38 sex-specific genes, with 27 linked to novel AD loci and 77% showing persistent sex heterogeneity.

Conclusions:

  • Sex-stratified GWAS and PWAS revealed significant sex-specific AD loci and genes with high concordance across ancestries.
  • Findings enhance understanding of AD pathogenesis and risk, identifying potential targets for sex-specific drug development.
  • Results support personalized medicine approaches for Alzheimer's disease based on sex-specific factors.