, Volume 38, Issue 5–6, pp 495–503 | Cite as

Effects of the APOE ε4 allele and education on cognitive function in Japanese centenarians

  • Yoshiko Lily IshiokaEmail author
  • Yasuyuki Gondo
  • Noriyuki Fuku
  • Hiroki Inagaki
  • Yukie Masui
  • Michiyo Takayama
  • Yukiko Abe
  • Yasumichi Arai
  • Nobuyoshi Hirose
Original Article


Apolipoprotein E (APOE) ε4 allele and education have been reported to affect the cognitive function in young-old adults. However, the effects and interactions of the ε4 allele and education on cognitive function in very old age, particularly in centenarians, are not well known. We studied 542 Japanese centenarians. Using the data in total of 452 participants (74 men and 378 women, mean age 103.6 ± 3.2 years) who were genotyped and assessed cognitive function with the Mini-Mental States Examination (MMSE), we examined the effects and interactions of the ε4 allele and education on the MMSE score. First, we coded education as three levels: low, middle, and high based on the formal educational levels (analysis 1). Second, to clarify the modifying effect of education, we adopted a new coding for education into two levels, considering a periodical background (around 1900) of gender differences in educational attainments (analysis 2). In analysis 1, the main effects of the ε4 allele and education on the MMSE score were significant after adjusting for age. Further, there was a significant three-way interaction effect between the ε4 allele, education, and gender on the MMSE. Analysis 2 showed that the modifying effect of the ε4 allele by education was observed only in women with the ε4 allele. These findings suggest that both the APOE ε4 allele and education appear to be associated with cognitive function even in centenarians, but the interaction between the ε4 allele and education might depend on gender in this cohort.


Gene–environment interaction APOE Cognition Centenarian 



We thank the participants for their time and personal information and Ms. Miho Shimura for her kind assistance. In addition to the authors, the following contributed to data acquisition as the TCS and JSS investigators: Ken Yamamura, MD, PhD; Yoshinori Ebihara, MD, PhD; Ken’ichiro Shimizu, MD, PhD; Susumu Nakazawa, MD; Toshio Kojima, MD, PhD; Koji Kitagawa. We also give our sincere thanks for his useful discussions to Prof. Peter Martin, PhD from Iowa State University. This study was funded by the grant from the Ministry of Health, Welfare, and Labor for the Scientific Research Project for Longevity, the Grant-in-Aid for Scientific Research (C) (No 2059706, 21590775, 24590898), the Grant-in-Aid for Young Scientist (B) (No. 15730346), and the Grant-in-Aid for challenging Exploratory Research (No. 24653194) from Japan Society for the Promotion of Science, by the grant from the Takeda Science Foundation, by the grant from Japan Health Foundation for the Prevention of Chronic Disease and the Improvement of QOL of Patients, by the grant from Foundation for Total Health Promotion, and by the grant from the Chiyoda Mutual Life Foundation.

Compliance with ethical standards

For participation in any of the studies, written informed consent was obtained either from the participants or by proxy when individuals lacked the capacity to consent. TCS and JSS were approved by the Ethical Committee of the Keio University School of Medicine and Tokyo Metropolitan Institute of Gerontology.


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Copyright information

© American Aging Association 2016

Authors and Affiliations

  • Yoshiko Lily Ishioka
    • 1
    Email author
  • Yasuyuki Gondo
    • 2
  • Noriyuki Fuku
    • 3
  • Hiroki Inagaki
    • 1
  • Yukie Masui
    • 1
  • Michiyo Takayama
    • 4
  • Yukiko Abe
    • 4
  • Yasumichi Arai
    • 4
  • Nobuyoshi Hirose
    • 4
  1. 1.Tokyo Metropolitan Institute of GerontologyItabashi-kuJapan
  2. 2.Graduate School of Human SciencesOsaka UniversityOsakaJapan
  3. 3.Graduate School of Health and Sports ScienceJuntendo UniversityChibaJapan
  4. 4.Center for Supercentenarian Medical Research, School of MedicineKeio UniversityTokyoJapan

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