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Basic Science and Pathogenesis.

Anatoliy I Yashin1,2, Deqing Wu1, Hongzhe Duan1

  • 1Social Science Research Institute, Duke University, Durham, NC, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

Genetic variations in HLA-C influence Alzheimer's disease (AD) risk, particularly in mothers with the APOE4 gene. This suggests HLA-C may modify APOE4's impact on AD development, highlighting immune system roles.

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Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • APOE4 is the primary genetic risk factor for late-onset Alzheimer's disease (AD), with a more significant impact on females.
  • The immune system, including natural killer (NK) and CD8+ T cells, plays a crucial role in AD pathogenesis.
  • Investigating genetic modulators of immune responses in AD is essential for understanding disease mechanisms.

Purpose of the Study:

  • To investigate how Human Leucocyte Antigen-C (HLA-C) gene polymorphisms influence Alzheimer's disease (AD) risk in individuals carrying the APOE4 allele.
  • To determine if HLA-C variations differentially affect AD risk in males and females, particularly in relation to maternal and paternal inheritance of APOE4.

Main Methods:

  • Utilized UK Biobanks (UKB) data to assess the association between HLA-C genetic variations and AD risk in offspring of APOE4 carriers.
  • Employed logistic regression models using REGENIE and PLINK2 software for statistical analysis.
  • Applied PLINK2 clumping to reduce the number of statistical tests and refine associations.

Main Results:

  • Specific HLA-C single nucleotide polymorphisms (SNPs) (rs2074488, rs2074491) were significantly associated with a reduced risk of AD in mothers carrying at least one APOE4 allele.
  • Other HLA-C SNPs (rs13203722, rs13218306, rs12207404) showed deleterious associations with AD in mothers.
  • No significant associations were found between HLA-C genetic variants and AD risk in fathers.

Conclusions:

  • HLA-C genetic variants may modulate the impact of the APOE4 allele on Alzheimer's disease (AD) occurrence, particularly in maternal inheritance.
  • These findings support the involvement of immune responses, potentially triggered by infections, in AD pathogenesis.
  • Further research into HLA-C's role could identify novel therapeutic targets for AD.