. 2024 Apr 3;112(7):1110-1116.e5.

doi: 10.1016/j.neuron.2024.01.008. Epub 2024 Jan 31.

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

Augustine Chemparathy¹, Yann Le Guen², Sunny Chen³, Eun-Gyung Lee³, Lesley Leong³, John E Gorzynski⁴, Tanner D Jensen⁴, Alexis Ferrasse⁴, Guangxue Xu⁴, Hong Xiang⁴, Michael E Belloy¹, Nandita Kasireddy¹, Andrés Peña-Tauber¹, Kennedy Williams¹, Ilaria Stewart¹, Lia Talozzi¹, Thomas S Wingo⁵, James J Lah⁶, Suman Jayadev⁷, Chadwick M Hales⁸, Elaine Peskind⁹, Daniel D Child¹⁰, Sigrun Roeber¹¹, C Dirk Keene¹⁰, Le Cong⁴, Euan A Ashley¹², Chang-En Yu¹³, Michael D Greicius¹⁴

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
³ Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Emory University School of Medicine, Atlanta, GA, USA; Goizueta Alzheimer's Disease Center, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Department of Neurology, University of Washington, Seattle, WA, USA.
⁸ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, University of Washington, Seattle, WA, USA.
⁹ Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹¹ Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Munich, Germany.
¹² Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: greicius@stanford.edu.

PMID: 38301647
PMCID: PMC10994769 (available on 2025-04-03)
DOI: 10.1016/j.neuron.2024.01.008

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

Augustine Chemparathy et al. Neuron. 2024.

. 2024 Apr 3;112(7):1110-1116.e5.

doi: 10.1016/j.neuron.2024.01.008. Epub 2024 Jan 31.

Authors

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
³ Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
⁴ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Emory University School of Medicine, Atlanta, GA, USA; Goizueta Alzheimer's Disease Center, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
⁷ Department of Neurology, University of Washington, Seattle, WA, USA.
⁸ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, University of Washington, Seattle, WA, USA.
⁹ Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
¹¹ Center for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Munich, Germany.
¹² Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: greicius@stanford.edu.

PMID: 38301647
PMCID: PMC10994769 (available on 2025-04-03)
DOI: 10.1016/j.neuron.2024.01.008

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.

Keywords: Alzheimer’s disease; apolipoprotein E; dementia; human genetics; long-read sequencing; loss of function; neurodegenerative disorders; structural variant.

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Conflict of interest statement

Declaration of interests L.C. reports relationships with Moderna, PossibleMedicines, AcrobatGenomics, ArborBiotechnology, CureGenetics, and RootpathGenomics that include consulting service, equity, or stocks.

Update of

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology.
Chemparathy A, Guen YL, Chen S, Lee EG, Leong L, Gorzynski J, Xu G, Belloy M, Kasireddy N, Tauber AP, Williams K, Stewart I, Wingo T, Lah J, Jayadev S, Hales C, Peskind E, Child DD, Keene CD, Cong L, Ashley E, Yu CE, Greicius MD. Chemparathy A, et al. medRxiv [Preprint]. 2023 Jul 24:2023.07.20.23292771. doi: 10.1101/2023.07.20.23292771. medRxiv. 2023. Update in: Neuron. 2024 Apr 3;112(7):1110-1116.e5. doi: 10.1016/j.neuron.2024.01.008. PMID: 37547016 Free PMC article. Updated. Preprint.

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

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

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