EIF2AK3 variants in Dutch patients with Alzheimer's disease

Tsz Hang Wong, Sven J. van der Lee, Jeroen G.J. van Rooij, Lieke H.H. Meeter, Petra Frick, Shamiram Melhem, Harro Seelaar, M. Arfan Ikram, Annemieke J. Rozemuller, Henne Holstege, Marc Hulsman, Andre Uitterlinden, Manuela Neumann, Jeroen J.M. Hoozemans, Cornelia M. van Duijn, Rosa Rademakers, John C. van Swieten*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

Original languageEnglish
Pages (from-to)229.e11-229.e18
JournalNeurobiology of Aging
Publication statusPublished - 1 Jan 2019


  • Alzheimer's disease
  • EIF2AK3
  • Exome sequencing
  • PERK
  • eIF-2 Kinase/genetics
  • Genetic Association Studies
  • Alzheimer Disease/genetics
  • Humans
  • Middle Aged
  • Male
  • Risk
  • Genetic Variation/genetics
  • Whole Exome Sequencing
  • Netherlands
  • Hippocampus/metabolism
  • Female
  • Aged


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