Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses

Neurobiol Aging. 2021 Sep;105:378.e1-378.e9. doi: 10.1016/j.neurobiolaging.2021.04.011. Epub 2021 Apr 24.


For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Utilizing a comprehensive neuropsychology battery, multivariate multiple regression was used to assess the influence of APOE carrier status and disease cohort on performance across five cognitive domains. Irrespective of disease cohort, E4 carriers had significantly lower performance in verbal memory and visuospatial domains than those with E3/3, while E2 carriers' cognitive performance was not significantly different. However, E2 carriers with frontotemporal dementia (FTD) performed significantly worse than those with E3/3 in the attention/working memory, executive function, and visuospatial domains. Our results highlight that the influence of APOE variation on cognition is complex, in some cases varying based on diagnosis and possibly underlying disease pathology.

Keywords: APOE; Cognitive impairment; E2; E4; Neurodegenerative disease; Neuropsychology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apolipoprotein E2 / genetics*
  • Apolipoprotein E4 / genetics*
  • Attention
  • Cognition*
  • Cognitive Dysfunction / diagnosis*
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / psychology
  • Cohort Studies
  • Executive Function
  • Female
  • Genetic Association Studies*
  • Genetic Variation / genetics*
  • Heterozygote
  • Humans
  • Male
  • Memory, Short-Term
  • Middle Aged
  • Neurodegenerative Diseases / complications*
  • Neurodegenerative Diseases / psychology
  • Neuropsychological Tests


  • Apolipoprotein E2
  • Apolipoprotein E4

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