Sex-Dependent Effects of the APOE ϵ4 Allele on Behavioral Traits and White Matter Structures in Young Adults

Hikaru Takeuchi, Hiroaki Tomita, Ryan Browne, Yasuyuki Taki, Yoshie Kikuchi, Chiaki Ono, Zhiqian Yu, Rui Nouchi, Ryoichi Yokoyama, Yuka Kotozaki, Seishu Nakagawa, Atsushi Sekiguchi, Kunio Iizuka, Sugiko Hanawa, Tsuyoshi Araki, Carlos Makoto Miyauchi, Kohei Sakaki, Takayuki Nozawa, Shigeyuki Ikeda, Susumu YokotaDaniele Magistro, Yuko Sassa, Ryuta Kawashima

Research output: Contribution to journalArticlepeer-review


The APOE ϵ4 allele is associated with a risk of Alzheimer's disease in the elderly, with the association being pronounced in females. Conversely, findings of the effects of the APOE ϵ4 allele in young adults are mixed. Here, we investigated the sex-genotype interaction effects of the APOE ϵ4 allele on cognitive functions as well as brain structures among 1258 young adults. After adjusting for multiple comparisons, there were significant effects of the interaction between sex and the number of APOE ϵ4 allele on some speed tasks (e.g., simple processing speed tasks and the reverse Stroop task) as well as on regional white matter volume (rWMV). The observed sex-genotype interaction conferred better cognitive performance and greater rWMV in the anterior frontal and precentral white matter areas in females having more APOE ϵ4 alleles and reduced rWMV in the same areas in male having more APOE ϵ4 alleles. These findings support the long-debated antagonistic pleiotropic effects of the APOE ϵ4 allele in females.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalCerebral Cortex
Issue number1
Publication statusPublished - 2021 Jan 1
Externally publishedYes


  • APOE genotype
  • imaging genetics
  • sex interaction effects
  • white matter structures
  • young adults

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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