ArticleNeuron2024
APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology.
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Article in Neuron, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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31 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- The role of APOE ε4 in modulating the relationship between non-genetic risk factors and dementia: a system review and meta-analysis.Journal of neurology · 2025Pooled it
- Article
- Protective mutations associated with APOE in Alzheimer's disease.Molecular psychiatry · 2026Review
- Apolipoprotein E Deficiency Impairs Human Microglial Proliferation Accompanied by Elevated Cellular Oxidative Stress.Journal of cellular and molecular medicine · 2026Article
- A quantitative trait locus for reduced microglial APOE expression associates with reduced cerebral amyloid angiopathy.Nature genetics · 2026Article
- ApoE expression across the CNS: Who, What, Where, When, and How (much)?Molecular neurodegeneration advances · 2026Review
- Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Health effects of loss of function variants in gene targets for Alzheimer's disease prevention.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer's Disease Pathogenesis.Biochemistry · 2025Article
- Netrin-1 as a molecular mediator linking APOE ε4 to alzheimer's disease pathogenesis.Scientific reports · 2025Article
- Trends and challenges of AAV-delivered gene editing therapeutics for CNS disorders: Implications for neurodegenerative disease.Molecular therapy. Nucleic acids · 2025Review
- Astrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons.Small science · 2025Review
- A manifesto for Alzheimer's disease drug discovery in the era of disease-modifying therapies.Molecular neurodegeneration · 2025Review
- Protective genetic variants against Alzheimer's disease.The Lancet. Neurology · 2025Review
- APOE4 carriers display loss of anticipatory cerebrovascular regulation across the Alzheimer's disease continuum.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- The impact of rare genetic variants on Alzheimer disease.Nature reviews. Neurology · 2025Review
- Suppressing APOE4-induced neural pathologies by targeting the VHL-HIF axis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- APOE genotype-dependent differences in human astrocytic energy metabolism.Frontiers in cellular neuroscience · 2025Article
- AAVrh.10 delivery of novel APOE2-Christchurch variant suppresses amyloid and Tau pathology in Alzheimer's disease mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Is the Relationship Between Cardiovascular Disease and Alzheimer's Disease Genetic? A Scoping Review.Genes · 2024Article
Corrections and comments
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Authors and funding
28 authors at 7 institutions in 2 countries.
Augustine ChemparathyDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Yann Le GuenDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, USA.
Sunny ChenGeriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
Eun-Gyung LeeGeriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
Lesley LeongGeriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
John E GorzynskiDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Tanner D JensenDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Alexis FerrasseDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Guangxue XuDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Hong XiangDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Michael E BelloyDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Nandita KasireddyDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Andrés Peña-TauberDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Kennedy WilliamsDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Ilaria StewartDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Lia TalozziDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Thomas S WingoEmory University School of Medicine, Atlanta, GA, USA; Goizueta Alzheimer's Disease Center, Emory University School of Medicine, Atlanta, GA, USA.
James J LahDepartment of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Suman JayadevDepartment of Neurology, University of Washington, Seattle, WA, USA.
Chadwick M HalesDepartment of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, University of Washington, Seattle, WA, USA.
Elaine PeskindVeterans 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.
Daniel D ChildDepartment of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
Sigrun RoeberCenter for Neuropathology and Prion Research, Faculty of Medicine, LMU Munich, Munich, Germany.
C Dirk KeeneDepartment of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
Le CongDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Euan A AshleyDepartment 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.
Chang-En YuGeriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
Michael D GreiciusDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. Electronic address: greicius@stanford.edu.
Stanford University · USUniversity of Washington · USEmory University · USGeriatric Research Education and Clinical Center · USVA Puget Sound Health Care System · USLudwig-Maximilians-Universität München · DEUniversity of Puget Sound · US
Funding
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MTranslational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergicsU19AG066567 · NIA · KAISER FOUNDATION RESEARCH INSTITUTE · PI CHRISTOPHER DIRK KEENE · 2021 to 2026
$80.4MINSTITUTIONAL TRAINING GRANT IN GENOME SCIENCET32HG000044 · NHGRI · STANFORD UNIVERSITY · PI MICHAEL P. SNYDER · 1995 to 2026
$32.2MUniversity of Washington Alzheimer's Disease Research CenterP30AG066509 · NIA · UNIVERSITY OF WASHINGTON · PI Thomas J. Grabowski · 2020 to 2026
$29.0MThe Goizueta Alzheimer's Disease Research CenterP30AG066511 · NIA · EMORY UNIVERSITY · PI Amy D Rodriguez · 2020 to 2026
$29.0MStanford Alzheimer's Disease Research CenterAdmin Supp: Developing iPSC models for AD and PDP30AG066515 · NIA · STANFORD UNIVERSITY · PI ELIZABETH MORMINO · 2020 to 2026
$29.0MSocial Determinants of Health, Race/Ethnicity, and White Matter HyperintensitiesP30AG066506 · NIA · UNIVERSITY OF FLORIDA · PI David E Vaillancourt · 2020 to 2026
$25.6MUC Davis Alzheimer's Disease Research CenterP30AG072972 · NIA · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Charles DeCarli, Rachel A Whitmer · 2021 to 2026
$25.2MNeurobehavior, Neuropathology, and Risk Factors in Alzheimer's DiseaseT32AG052354 · NIA · UNIVERSITY OF WASHINGTON · PI Brian C. Kraemer, ELAINE R. PESKIND · 2016 to 2026
$6.7MIlluminating the APOE Locus with Long-Read Sequencing and Targeted GenomicsR35AG072290 · NIA · STANFORD UNIVERSITY · PI GREICIUS, MICHAEL D · 2021 to 2025
$4.6MThe Stanford Extreme Phenotypes in Alzheimer's Disease (StEP AD) CohortR01AG060747 · NIA · STANFORD UNIVERSITY · PI GREICIUS, MICHAEL D · 2018 to 2022
$3.4MRecombineering-based no-cleavage gene-editing toolkit for large-scale genome engineering and functional screeningR01GM141627 · NIGMS · STANFORD UNIVERSITY · PI Le Cong · 2021 to 2026
$3.3MBLRD VA I01 BX000933BLRD VA I01 BX004823NHGRI NIH HHS R35 HG011316NHGRI NIH HHS T32 HG000044NIA NIH HHS K99 AG075238NIA NIH HHS P30 AG066506NIA NIH HHS P30 AG066509NIA NIH HHS P30 AG066511NIA NIH HHS P30 AG066515NIA NIH HHS P30 AG072972NIA NIH HHS R00 AG075238NIA NIH HHS R01 AG060747NIA NIH HHS R35 AG072290NIA NIH HHS T32 AG052354NIA NIH HHS U19 AG066567NIA NIH HHS U24 AG021886NIGMS NIH HHS R01 GM141627
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.
Indexed as
Alzheimer DiseaseAllelesApolipoprotein E4Apolipoproteins EGenotypeHumansLongevityApoE protein, humanApolipoprotein E4Apolipoproteins EAlzheimer’s diseaseapolipoprotein Edementiahuman geneticslong-read sequencingloss of functionneurodegenerative disordersstructural variant
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