APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology

Augustine Chemparathy, Yann Le Guen, Sunny Chen, Eun Gyung Lee, Lesley Leong, John E. Gorzynski, Tanner D. Jensen, Alexis Ferrasse, Guangxue Xu, Hong Xiang, Michael E. Belloy, Nandita Kasireddy, Andrés Peña-Tauber, Kennedy Williams, Ilaria Stewart, Lia Talozzi, Thomas S. Wingo, James J. Lah, Suman Jayadev, Chadwick M. HalesElaine Peskind, Daniel D. Child, Sigrun Roeber, C. Dirk Keene, Le Cong, Euan A. Ashley, Chang En Yu, Michael D. Greicius

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71–90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

Original languageEnglish
Pages (from-to)1110-1116.e5
JournalNeuron
Volume112
Issue number7
DOIs
StatePublished - Apr 3 2024

Keywords

  • Alzheimer's disease
  • apolipoprotein E
  • dementia
  • human genetics
  • long-read sequencing
  • loss of function
  • neurodegenerative disorders
  • structural variant

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