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[Preprint]. 2023 Jul 24:2023.07.20.23292771.
doi: 10.1101/2023.07.20.23292771.

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

Augustine Chemparathy  1 , Yann Le Guen  1   2 , Sunny Chen  3 , Eun-Gyung Lee  3 , Lesley Leong  3 , John Gorzynski  4 , Guangxue Xu  5 , Michael Belloy  1 , Nandita Kasireddy  1 , Andrés Peña Tauber  1 , Kennedy Williams  1 , Ilaria Stewart  1 , Thomas Wingo  6   7 , James Lah  8 , Suman Jayadev  9 , Chad Hales  6   7 , Elaine Peskind  10   11 , Daniel D Child  12 , C Dirk Keene  12 , Le Cong  5 , Euan Ashley  4   13   14 , Chang-En Yu  3   15 , Michael D Greicius  1
Affiliations

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

Augustine Chemparathy et al. medRxiv. .

Update in

Abstract

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele 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 older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.

Keywords: Alzheimer’s Disease; Apolipoprotein E; Human genetics; Loss-of-function; Neurodegenerative disorders.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. APOE loss-of-function carrier demographics and variant positions
(a) Carrier demographics. Six carriers of high confidence APOE loss-of-function variants were identified among 26,605 older controls and 20,856 AD cases sequenced as part of the Alzheimer’s Disease Sequencing Project. (b) Three distinct single nucleotide polymorphisms and one structural variant were identified. Genomic coordinates are based on hg38.
Figure 2.
Figure 2.. Loss of APOE ε4 is associated with absent amyloid pathology and reduced tau pathology in a 90+ year-old control.
Subject 1 is a neuropathological outlier among age-matched ε3/ε4 individuals in their (a) CERAD staging of amyloid plaque density; (b) Thal staging of amyloid plaque regional distribution; (c) Cerebral amyloid angiopathy staging; and (d) Braak staging of neurofibrillary tangles (tau pathology).
See this image and copyright information in PMC

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