Apolipoprotein E homozygous ε4 allele status: Effects on cortical structure and white matter integrity in a young to mid-age sample

Eur Neuropsychopharmacol. 2021 May;46:93-104. doi: 10.1016/j.euroneuro.2021.02.006. Epub 2021 Feb 27.


Apolipoprotein E (APOE) genotype is the strongest single gene predictor of Alzheimer's disease (AD) and has been frequently associated with AD-related brain structural alterations before the onset of dementia. While previous research has primarily focused on hippocampal morphometry in relation to APOE, sporadic recent findings have questioned the specificity of the hippocampus and instead suggested more global effects on the brain. With the present study we aimed to investigate associations between homozygous APOE ε4 status and cortical gray matter structure as well as white matter microstructure. In our study, we contrasted n = 31 homozygous APOE ε4 carriers (age=34.47 years, including a subsample of n = 12 subjects with depression) with a demographically matched sample without an ε4 allele (resulting total sample: N = 62). Morphometry analyses included a) Freesurfer based cortical segmentations of thickness and surface area measures and b) tract based spatial statistics of DTI measures. We found pronounced and widespread reductions in cortical surface area of ε4 homozygotes in 57 out of 68 cortical brain regions. In contrast, no differences in cortical thickness were observed. Furthermore, APOE ε4 homozygous carriers showed significantly lower fractional anisotropy in the corpus callosum, the right internal and external capsule, the left corona radiata and the right fornix. The present findings support a global rather than regionally specific effect of homozygous APOE ε4 allele status on cortical surface area and white matter microstructure. Future studies should aim to delineate the clinical implications of these findings.

Keywords: Alzheimer's disease; Apolipoprotein E; DTI; FA; Structural MRI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / genetics
  • Apolipoprotein E4* / genetics
  • Apolipoproteins E / genetics
  • Brain / diagnostic imaging
  • Diffusion Tensor Imaging / methods
  • Genotype
  • Homozygote
  • Humans
  • Magnetic Resonance Imaging
  • White Matter* / diagnostic imaging


  • ApoE protein, human
  • Apolipoprotein E4
  • Apolipoproteins E