The effect of APOE genotype on Alzheimer's disease risk is influenced by sex and docosahexaenoic acid status

Neurobiol Aging. 2018 Sep:69:209-220. doi: 10.1016/j.neurobiolaging.2018.05.017. Epub 2018 May 21.


An apolipoprotein E ε4 (APOE-ε4) genotype is the strongest common genetic determinant of Alzheimer's disease (AD). The pleiotropic nature of apolipoprotein E has made elucidation of the aetiological basis difficult to establish, which is further complicated by the fact that the penetrance of the APOE-ε4 allele is modulated by sex, age, and nutrition. A greater metabolic consequence of the APOE-ε4 allele is likely to contribute to the fact that two-thirds of AD patients are female. A higher tissue status of the marine n-3 fatty acid docosahexaenoic acid (DHA) is associated with a lower AD risk. However, APOE-ε4 carriers appear less sensitive to the neurocognitive benefits, which may be due to defective blood-brain barrier transport of DHA exacerbated by aging and possibly sex. This suggests higher DHA requirements in this large population subgroup. This narrative review will consider the influence of sex and DHA in modulating APOE-ε4-mediated AD risk.

Keywords: Apolipoprotein E; Blood-brain barrier; Docosahexaenoic acid; Lipid metabolism; Lipid transport; Polyunsaturated fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Animals
  • Apolipoprotein E4 / genetics*
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism*
  • Docosahexaenoic Acids / metabolism*
  • Genetic Predisposition to Disease*
  • Genotype
  • Gonadal Steroid Hormones / metabolism
  • Humans
  • Menopause
  • Risk Factors
  • Sex Factors


  • Apolipoprotein E4
  • Gonadal Steroid Hormones
  • Docosahexaenoic Acids