Contribution of APOE genome mosaicism to sporadic Alzheimer’s disease

Apolipoprotein E (ApoE) 4 is the major genetic risk factor for sporadic Alzheimer’s disease (AD). Three common apoE isoforms result from differences in cysteine and arginine at positions 112 and 158:

  • apoE3 contains a cysteine at 112 and an arginine at position 158
  • apoE2 contains two cysteines at each site
  • apoE4 contains two arginines at each site.

ApoE2 may provide some protection against the disease. ApoE3, the most common allele, is believed to have a neutral effect on the disease. Having at least one apoE4 gene doubles or triples the risk of getting AD or having two apoE4 genes increases the risk of getting AD even more – about 8- to 12-fold. Genomic mosaicism arising from postzygotic mutations has long been associated with cancer and, more recently, with non-cancer diseases.

Our laboratory found that some AD patients carried a higher dose of the apoE4 gene than they should have. This phenomenon may be attributed to age-associated somatic mutations and represents a type of genomic mosaicism. We also found that this genome mosaicism occurs in a specific subset of human blood immune cells, that is, human CD14+CD16+ intermediate monocytes. The function of this cell involves immune surveillance, phagocytosis and removal of pathogenic microorganisms, dead cells and abnormally folded proteins including amyloid β (Aβ), which is one of the main drivers in the early stage of AD.

We know that the interaction between apoE and Aβ appears to depend on the apoE isoforms and its lipidation state. The apoE4/Aβ complex is less stable compared with other isoforms. Although the mechanism is unclear, we speculate that mutational pressure may lead to higher apoE4 gene dose accumulation in human intermediate monocytes, and unstable apoE4 and Aβ binding interfere with monocyte clearance of Aβ. The purpose of this study is to identify single-nucleotide mosaicisms (SNMs) at sites 112 and 158 of the apoE4 gene in patients with AD and their association with the progression of AD through third-generation sequencing technology.


  • Identify APOE SNMs at sites 112 and 158 from the post-mortem human brain Pac-Bio deep sequencing data.
  • Test the effect of apoE4 gene dose on its association with AD progression.

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