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Basic Science and Pathogenesis.

Ting-Chen Wang1,2, Jigyasha Timsina3,4, Chenyang Jiang5,6,7

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This study found novel female-specific genetic associations for Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). These findings emphasize the importance of sex-specific genetic analyses for understanding AD.

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Area of Science:

  • Genetics
  • Neuroscience
  • Biomarkers

Background:

  • Cerebrospinal fluid (CSF) biomarkers like amyloid-β 42 (Aβ42) are crucial for Alzheimer's disease (AD) genome-wide association studies (GWAS).
  • Understanding AD biological processes requires analysis beyond traditional case-control studies.
  • This study utilizes the largest sample size to date (N=18,491) for sex-stratified GWAS of CSF biomarkers.

Purpose of the Study:

  • To identify sex-specific genetic associations with AD pathology.
  • To perform sex-stratified genome-wide association studies (GWAS) on Aβ42, Tau, and phosphorylated tau (pTau181) CSF biomarkers.
  • To elucidate the genetic architecture of AD by considering sex differences.

Main Methods:

  • Conducted meta-analyses of sex-stratified GWAS across 22 US and European cohorts (N=6,785) and six external cohorts (N=11,706).
  • Applied consistent quality control and z-score standardization for CSF biomarker values.
  • Adjusted GWAS for age, principal components of genetic ancestry, and cohort-array combinations.

Main Results:

  • Identified seven genome-wide significant loci, including three novel female-specific associations.
  • Discovered a novel female-specific association for Aβ42 (rs372578) and Tau (rs1582763).
  • Found a novel female-specific association for pTau181 (rs6434518), linked to immune response and lipid metabolism genes.

Conclusions:

  • Highlighted significant female-specific genetic associations for CSF biomarkers in AD.
  • Emphasized the critical role of sex-specific genetic analyses in understanding AD.
  • Advanced the comprehension of AD genetic architecture by revealing sex-based differences.