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Basic Science and Pathogenesis.

Alexander M Kulminski1, Fan Feng1, Irina Kulminskaya1

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

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Summary
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Genetic susceptibility to Alzheimer's disease (AD) and diabetes mellitus (DM) shows significant sex differences. Genome-wide association studies reveal distinct genetic loci influencing AD and DM risk in men and women, highlighting the role of genetic heterogeneity.

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Area of Science:

  • Genetics
  • Neuroscience
  • Endocrinology

Background:

  • Alzheimer's disease (AD) affects women more than men, but survival rates don't fully explain this disparity.
  • Genetic factors significantly contribute to AD heritability, necessitating research into sex-specific genetic influences on AD and its risk factors.
  • Understanding sex differences in AD and diabetes mellitus (DM) susceptibility can elucidate disease mechanisms.

Purpose of the Study:

  • To investigate sex-specific genetic architectures of Alzheimer's disease (AD) and diabetes mellitus (DM) using genome-wide association studies (GWAS).
  • To identify sex-specific genetic loci and pleiotropic effects influencing susceptibility to AD and DM in European populations.
  • To explore the role of the APOE gene in sex-specific risks for AD and DM.

Main Methods:

  • Conducted genome-wide association studies (GWAS) and pleiotropic meta-analyses for AD and DM in European men and women.
  • Analyzed large cohorts: 172,097 men and 204,904 women for AD; 165,287 men and 195,190 women for DM.
  • Leveraged strong genetic associations with DM to identify weaker associations with AD, focusing on sex-specific effects.

Main Results:

  • Identified 30 men-specific DM loci with pleiotropic effects on AD in gene clusters like THADA and IGF2BP2.
  • Discovered 16 women-specific DM loci with pleiotropic effects on AD in gene clusters including HNF1B and CDKN2B.
  • Female APOE ε4 carriers had higher AD risk (β=1.29) than males (β=1.12); APOE ε4 favorably associated with DM in both sexes without significant sex difference.

Conclusions:

  • Genetic susceptibility to DM and AD is more pronounced in men.
  • Antagonistic effects of APOE ε4 on AD and DM, along with sex-specific differences, underscore the importance of APOE-related genetic heterogeneity in AD-DM risk.
  • Sex-specific genetic factors play a critical role in the differential susceptibility to Alzheimer's disease and diabetes mellitus.