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Basic Science and Pathogenesis.

Donghe Li1, Sarang Kang2, Kun Ho Lee3,4,5

  • 1Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.

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

The apolipoprotein E (APOE) gene significantly impacts Alzheimer's disease (AD) risk and related traits. Increased APOE4 alleles are linked to higher AD risk and cognitive decline, while APOE2 shows a protective effect.

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Area of Science:

  • Neurogenetics
  • Alzheimer's Disease Research
  • Population Genetics

Background:

  • Apolipoprotein E (APOE) is a key genetic risk factor for Alzheimer's disease (AD).
  • Common APOE alleles (APOE2, APOE3, APOE4) are well-studied, but rare missense variants (RMVs) also contribute to AD risk.
  • Investigating APOE variants in East Asian populations is crucial due to potential ancestry-specific effects.

Purpose of the Study:

  • To analyze the association of common APOE genotypes and allelic doses with Alzheimer's disease (AD) and related traits in a South Korean cohort.
  • To investigate the impact of APOE rare missense variants (RMVs) on AD and related traits.
  • To conduct meta-analyses including diverse Asian cohorts to strengthen findings.

Main Methods:

  • Analysis of the Gwangju Alzheimer's and Related Dementias (GARD) cohort (over 16,000 participants).
  • Evaluation of APOE common genotypes and allelic doses (E2, E4) for associations with AD, cognitive function, and brain MRI measures.
  • Investigation of APOE RMVs and meta-analyses with other large Asian cohorts (ACAD, ADGC, UKBB).

Main Results:

  • APOE allelic dose analysis revealed significant associations: increased APOE4 alleles correlated with higher AD odds (OR: 2.36) and cognitive decline.
  • APOE2 alleles showed a protective effect (OR: 0.83) with no significant impact on cognitive domains.
  • Higher APOE4 allele counts were associated with reduced hippocampal volume and entorhinal cortex thickness.

Conclusions:

  • APOE genotypes and allelic doses significantly influence Alzheimer's disease (AD) risk and related traits.
  • Comprehensive analysis of common and rare APOE variants in diverse populations, especially East Asians, is vital for AD understanding and treatment.
  • Findings highlight the critical role of APOE in AD pathogenesis across different ancestries.