Synergistic Effects of APOE and CLU May Increase the Risk of Alzheimer's Disease: Acceleration of Atrophy in the Volumes and Shapes of the Hippocampus and Amygdala

J Alzheimers Dis. 2021;80(3):1311-1327. doi: 10.3233/JAD-201162.


Background: The volume loss of the hippocampus and amygdala in non-demented individuals has been reported to increase the risk of developing Alzheimer's disease (AD). Many neuroimaging genetics studies mainly focused on the individual effects of APOE and CLU on neuroimaging to understand their neural mechanisms, whereas their synergistic effects have been rarely studied.

Objective: To assess whether APOE and CLU have synergetic effects, we investigated the epistatic interaction and combined effects of the two genetic variants on morphological degeneration of hippocampus and amygdala in the non-demented elderly at baseline and 2-year follow-up.

Methods: Besides the widely-used volume indicator, the surface-based morphometry method was also adopted in this study to evaluate shape alterations.

Results: Our results showed a synergistic effect of homozygosity for the CLU risk allele C in rs11136000 and APOEɛ4 on the hippocampal and amygdalar volumes during a 2-year follow-up. Moreover, the combined effects of APOEɛ4 and CLU C were stronger than either of the individual effects in the atrophy progress of the amygdala.

Conclusion: These findings indicate that brain morphological changes are caused by more than one gene variant, which may help us to better understand the complex endogenous mechanism of AD.

Keywords: APOE; CLU; morphometry; subcortical structures; synergistic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology*
  • Amygdala / pathology*
  • Apolipoproteins E / genetics*
  • Atrophy / pathology
  • Clusterin / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Hippocampus / pathology*
  • Humans
  • Male
  • Polymorphism, Single Nucleotide


  • ApoE protein, human
  • Apolipoproteins E
  • CLU protein, human
  • Clusterin