Affinage

APOE

Apolipoprotein E · UniProt P02649

Round 2 corrected
Length
317 aa
Mass
36.2 kDa
Annotated
2026-04-28
130 papers in source corpus 21 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Apolipoprotein E is a secreted lipid-transport protein that serves as a high-affinity ligand for the LDL receptor family (LDLR, LRP1, apoER2), mediating cellular cholesterol uptake and redistribution, and whose three common isoforms (E2, E3, E4) differ by single amino acid substitutions that profoundly alter receptor-binding affinity, lipoprotein particle formation via ABCA1, and disease risk (PMID:3283935, PMID:11701639, PMID:14754908). In the brain, ApoE regulates amyloid-β clearance by competing with Aβ for LRP1-dependent uptake, serves as a direct ligand for the microglial receptor TREM2 to facilitate Aβ/lipoprotein phagocytosis, and exacerbates tau-mediated neurodegeneration through isoform-dependent microglial neuroinflammation, with ApoE4 consistently conferring the greatest pathological burden (PMID:23620513, PMID:27477018, PMID:28930663, PMID:29861287, PMID:28959956). ApoE4 also disrupts blood–brain barrier integrity through the cyclophilin A–MMP9 pericyte-injury pathway, promotes endolysosomal lipofuscinosis via LDLR-mediated uptake of polyunsaturated fatty acid–cholesteryl esters that enhance lysosomal tau fibril accumulation, and attenuates classical complement activation through picomolar-affinity binding to activated C1q (PMID:32376954, PMID:39532095, PMID:30692699). Beyond neurodegeneration, elevated APOE expression driven by mitochondrial electron-transport-chain dysfunction promotes cellular senescence by triggering autophagy-lysosomal degradation of nuclear lamina proteins and heterochromatin factor KAP1 (PMID:37117743, PMID:37171075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1988 High

    Establishing ApoE as an LDL receptor ligand central to lipid transport resolved its core molecular function and linked receptor-binding-defective mutations to familial type III hyperlipoproteinemia.

    Evidence Biochemical receptor-binding assays and mutant analysis in multiple tissues

    PMID:3283935

    Open questions at the time
    • Structural basis of receptor recognition not yet defined
    • Brain-specific functions uncharacterized
    • Isoform-specific functional consequences not yet delineated
  2. 1999 High

    Demonstration that ApoE3, but not ApoE4, protects neurons against excitotoxic and age-dependent neurodegeneration established isoform-specific neuroprotective functions independent of peripheral lipid metabolism.

    Evidence Human apoE isoform knock-in transgenic mice challenged with kainic acid, quantitative morphometry of synapses and dendrites

    PMID:10366621

    Open questions at the time
    • Downstream signaling pathway mediating neuroprotection unknown
    • Whether truncated apoE fragments contribute to neurotoxicity in vivo not settled
    • Mechanism by which E4 fails to protect not defined
  3. 2000 High

    Comprehensive functional characterization of all three isoforms consolidated the framework that single amino acid changes (Cys112Arg, Arg158Cys) produce divergent effects on receptor binding, neurite outgrowth, and disease susceptibility.

    Evidence Isoform-specific functional assays, genetic association studies, receptor-binding assays across multiple labs

    PMID:11701639

    Open questions at the time
    • Atomic-level structural basis for isoform-specific domain interactions unresolved
    • Isoform-specific signaling cascades not mapped
  4. 2004 High

    Mapping the LRP1-binding epitope to ApoE residues 130–155 with nanomolar affinity and identifying Lys143 as critical resolved the structural requirements for receptor engagement and heparin competition.

    Evidence Surface plasmon resonance, solution binding assays, and site-directed mutagenesis with soluble LRP domains

    PMID:15182176

    Open questions at the time
    • Full-length ApoE–LRP1 co-structure not available
    • Relative contribution of LRP1 vs LDLR binding in brain Aβ clearance unknown
  5. 2004 High

    Discovery that ApoE forms a direct complex with ABCA1 and requires ABCA1 lipid translocase activity for HDL-sized particle biogenesis established the mechanism by which ApoE acquires lipid for functional lipoprotein assembly.

    Evidence Radioligand competition binding, native gel analysis, cholesterol efflux assay, and Tangier disease mutant ABCA1 fibroblasts

    PMID:14754908

    Open questions at the time
    • Stoichiometry and structure of ApoE–ABCA1 complex not defined
    • Whether ABCA1-dependent lipidation differs by isoform in vivo uncertain
  6. 2013 High

    Demonstrating that ApoE regulates brain Aβ clearance by competing with Aβ for LRP1-dependent uptake—rather than through direct ApoE–Aβ complexes in extracellular fluid—fundamentally reframed the mechanism of ApoE's role in amyloid pathology.

    Evidence Brain microdialysis with apoE infusions in vivo, astrocyte uptake assays, size-exclusion chromatography of CSF

    PMID:23620513

    Open questions at the time
    • Whether competition mechanism operates equivalently across all brain regions not tested
    • Quantitative contribution of astrocytes vs microglia to Aβ clearance in this model unclear
  7. 2013 Medium

    Structural characterization of full-length apoE3 revealed inter-domain communication such that the single Cys112→Arg change in apoE4 propagates conformational changes to the C-terminal domain, providing a physical basis for isoform-specific differences.

    Evidence Biophysical characterization of recombinant full-length apoE protein

    PMID:24115173

    Open questions at the time
    • High-resolution co-crystal with receptors not obtained
    • Functional validation of proposed domain–domain interaction limited
  8. 2016 High

    Identification of TREM2 as a direct ApoE receptor on microglia—with AD-associated TREM2 mutations impairing binding—established a new axis linking ApoE to microglial phagocytic function and innate immunity in neurodegenerative disease.

    Evidence Unbiased protein microarray screen, co-IP, TREM2 KO and overexpression cellular assays, human TREM2-variant macrophages

    PMID:27477018

    Open questions at the time
    • ApoE–TREM2 binding interface not structurally resolved
    • Relative contribution of TREM2-dependent vs LRP1-dependent uptake in microglia not quantified
  9. 2017 High

    Linking the TREM2–APOE axis to a transcriptional switch from homeostatic to neurodegenerative microglial states across ALS, MS, and AD models generalized ApoE's role in microglial polarization beyond Alzheimer's disease.

    Evidence Single-cell transcriptomics in multiple mouse disease models, TREM2 KO and APOE KO genetic epistasis, phagocytosis assays

    PMID:28930663

    Open questions at the time
    • Whether restoring homeostatic microglial state is therapeutic in humans unknown
    • Whether ApoE isoforms differentially drive this transcriptional switch not tested in this study
  10. 2017 High

    Demonstrating that ApoE4 exacerbates tau-mediated neurodegeneration independently of Aβ—through enhanced microglial inflammatory reactivity—decoupled ApoE's pathogenic effects from the amyloid cascade.

    Evidence Human ApoE knock-in × P301S tau transgenic mice, neuron-glia co-culture with isoform-specific glia, TNF-α measurement

    PMID:28959956

    Open questions at the time
    • Molecular mechanism by which ApoE4 enhances microglial TNF-α production not defined
    • Whether ApoE absence is protective in human tauopathy unknown
  11. 2018 High

    Using isogenic iPSC-derived neurons, astrocytes, and microglia confirmed cell-type-specific ApoE4 pathologies (increased Aβ secretion, impaired Aβ uptake, cholesterol accumulation) in human cells and showed that CRISPR correction of E4 to E3 rescues these phenotypes.

    Evidence CRISPR/Cas9 isogenic iPSC lines, transcriptional profiling, Aβ secretion/uptake assays, cholesterol measurement, phagocytosis assays

    PMID:29861287

    Open questions at the time
    • Whether E4→E3 correction rescues in vivo brain pathology in humanized models not shown
    • Mechanism by which E4 increases neuronal synapse number unclear
  12. 2019 High

    Discovery that all ApoE isoforms bind activated C1q with picomolar affinity and attenuate classical complement cascade activation revealed a previously unrecognized immunomodulatory function of ApoE in both brain and vasculature.

    Evidence Surface plasmon resonance (KD ~140–580 pM), immunostaining of human Aβ plaques and atherosclerotic arteries, ApoE-KO mice with C5 siRNA rescue

    PMID:30692699

    Open questions at the time
    • Whether isoform differences in C1q binding affinity are functionally significant in vivo not resolved
    • Structural basis of ApoE–C1q interaction unknown
  13. 2020 High

    Demonstrating that APOE4 causes blood–brain barrier breakdown via the cyclophilin A–MMP9 pericyte pathway independently of Aβ/tau established a vascular mechanism for ApoE4-associated cognitive decline.

    Evidence Dynamic contrast-enhanced MRI for BBB permeability, CSF pericyte-injury biomarkers, PET amyloid/tau imaging in human subjects

    PMID:32376954

    Open questions at the time
    • Direct causal link between pericyte CypA–MMP9 and BBB permeability in humans not interventionally tested
    • Whether BBB breakdown is reversible with CypA inhibition in E4 carriers unknown
  14. 2022 High

    Showing that elevated APOE drives cellular senescence by promoting autophagy-lysosomal degradation of nuclear lamins and KAP1, destabilizing heterochromatin, extended ApoE's functional repertoire to chromatin regulation and aging.

    Evidence CRISPR-Cas9 APOE KO in human mesenchymal progenitor cells, autophagy-lysosomal pathway inhibitors, Western blot, chromatin analysis

    PMID:37117743

    Open questions at the time
    • Whether this senescence mechanism operates in neurons or astrocytes not tested
    • How APOE protein triggers autophagy-lysosomal degradation of nuclear lamina components mechanistically unclear
  15. 2023 High

    Identification of mitochondrial ETC dysfunction as a potent upstream driver of APOE transcriptional upregulation connected metabolic stress to ApoE-mediated inflammatory and neurodegenerative pathways.

    Evidence Gene editing and pharmacological inhibition of ETC complexes I/III/IV, iPSC-derived astrocytes, transcriptomics, 5xFAD mouse brain analysis

    PMID:37171075

    Open questions at the time
    • Transcription factors and cis-regulatory elements mediating ETC-dependent APOE induction not identified
    • Whether ETC dysfunction-driven APOE increase is sufficient to trigger downstream Aβ or senescence phenotypes not shown
  16. 2024 High

    Reconstituting ApoE isoform- and LDLR-dependent endolysosomal lipofuscinosis in human neurons—showing that PUFA-cholesteryl ester-loaded ApoE4 particles cause lipofuscin accumulation that enhances tau fibril retention—unified lipid metabolism and tau pathology in a single endolysosomal mechanism.

    Evidence iPSC-derived neurons, LDLR binding assays, lipofuscin quantification, tau fibril uptake, intrahippocampal injection in mice, Christchurch mutation analysis

    PMID:39532095

    Open questions at the time
    • Whether lipofuscinosis pathway is reversible or druggable not tested
    • Relative contribution of LDLR vs LRP1 in neuronal lipofuscin accumulation not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of ApoE isoform–receptor complexes, whether therapeutic modulation of TREM2–ApoE or CypA–MMP9 pathways can reverse ApoE4-driven pathology in humans, and the transcriptional mechanism linking mitochondrial dysfunction to APOE upregulation.
  • No high-resolution co-crystal structure of ApoE with any receptor
  • No interventional human trial targeting ApoE-specific pathogenic mechanisms
  • Transcriptional regulation of APOE by mitochondrial stress not mechanistically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0005764 lysosome 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ABCA1C1QLDLRLRP1LRP8TREM2

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 ApoE protein serves as a ligand for LDL receptors and participates in cholesterol and lipid transport among cells; a mutant form defective in LDL receptor binding causes familial type III hyperlipoproteinemia; ApoE is synthesized in liver, brain, spleen, and kidney and participates in cholesterol redistribution and repair responses to tissue injury. Biochemical characterization, receptor-binding assays, mutant analysis Science High 3283935
2000 ApoE is a multifunctional protein whose three isoforms (E2, E3, E4) differ by single amino acid substitutions with profound functional consequences: apoE2 is associated with type III hyperlipoproteinemia; apoE4 increases risk for atherosclerosis and Alzheimer's disease, impairs neurite outgrowth, and reduces cognitive function; isoform-specific differences in cellular signaling exist. Isoform-specific functional assays, genetic studies, receptor-binding assays Annual review of genomics and human genetics High 11701639
2004 ApoE peptides from the N-terminal receptor-binding domain (residues 130-149 and 141-155) bind directly to LRP1 (sLRP domains 2, 3, and 4) with KD values in the 100 nM range; mutation of Lys143 (but not Arg142) reduced binding 10-fold; both peptides also bind heparin, which competes for sLRP binding. Solution binding assays, surface plasmon resonance, mutagenesis Biochemistry High 15182176
2004 ApoE3 forms a direct complex with ABCA1 in fibroblasts; lipid-free apoE3 inhibits apoA-I binding to ABCA1 (IC50 ~2.5 µg/ml vs 12.3 for reconstituted HDL); ABCA1 lipid translocase activity is required for biogenesis of apoE-containing HDL-sized particles; the ABCA1 Tangier disease mutation C1477R abolished apoE3 binding and apoE3-mediated cholesterol efflux; all apoE isoforms showed similar ABCA1 binding and cholesterol efflux kinetics. Radioligand competition binding, cholesterol efflux assay, native gel analysis, mutant ABCA1 fibroblasts Journal of lipid research High 14754908
1999 ApoE3, but not apoE4, protects against excitotoxin-induced and age-dependent neurodegeneration in mouse brain; neuronal expression of apoE3 preserved synaptophysin-positive terminals, MAP2-positive dendrites, and neurofilament-positive axons after kainic acid challenge, whereas apoE4 did not provide this protection. Transgenic mouse model (NSE-promoter driven human apoE3 or E4 in Apoe-/- background), immunohistochemistry, quantitative morphometry The Journal of neuroscience High 10366621
1999 Truncated apoE (22 kDa N-terminal thrombin-cleavage fragment) and apoE-derived peptides cause intracellular calcium influx and hippocampal neuron death; these effects involve cell surface receptors and are reduced by receptor-associated protein (RAP) or NMDA receptor antagonist MK-801, and require extracellular calcium; protease inhibitors blocked full-length apoE toxicity but not truncated apoE toxicity, suggesting proteolytic fragments mediate apoE neurotoxicity. Primary neuron culture, calcium imaging, pharmacological inhibition (RAP, MK-801, calcium chelation), protease inhibitor treatment The Journal of neuroscience Medium 10436064
2003 ApoE3 particles stimulate nitric oxide (NO) release from endothelial cells in an isoform-dependent manner (apoE3 > apoE2 > apoE4); this effect is mediated through tyrosine phosphorylation of apoE receptor 2 (apoER2) and downstream PI3-kinase signaling to activate NO synthase. Fluorescent NO assay in cultured endothelial cells, PI3-kinase inhibitor treatment, tyrosine phosphorylation analysis of apoER2 FEBS letters Medium 12681505
2005 When associated with lipid, apoE4 preferentially binds intermediate aggregated forms of Aβ with higher avidity than apoE2 or apoE3; different Aβ conformations during spontaneous aggregation confer differing binding affinities to the three apoE isoforms. In vitro binding assays with lipid-associated apoE isoforms and Aβ in various aggregation states Sub-cellular biochemistry Medium 15709483
2013 ApoE and soluble Aβ interact minimally in solution and in human CSF; instead, apoE isoforms regulate sAβ metabolism in astrocytes and brain interstitial fluid by competing with Aβ for LRP1-dependent cellular uptake; this competition mechanism—not direct apoE/Aβ binding in extracellular fluids—accounts for apoE's regulation of Aβ clearance. Multiple biochemical and analytical techniques (size exclusion chromatography, native PAGE, ELISA), brain Aβ microdialysis in mice with apoE infusions, astrocyte uptake assays Proceedings of the National Academy of Sciences of the United States of America High 23620513
2017 The TREM2-APOE signaling pathway drives microglia from a homeostatic to a neurodegenerative phenotype in ALS, MS, and AD models; TREM2 induces APOE signaling after phagocytosis of apoptotic neurons; targeting the TREM2-APOE pathway restored homeostatic microglial signature and prevented neuronal loss; APOE-mediated neurodegenerative microglia lose tolerogenic function. Mouse models of ALS, MS, AD; single-cell transcriptomics; genetic manipulation (TREM2 KO, APOE KO); phagocytosis assays Immunity High 28930663
2017 ApoE4 exacerbates tau-mediated neurodegeneration independently of Aβ; P301S tau mice on an E4 background have higher brain tau levels, more somatodendritic tau redistribution, greater brain atrophy and neuroinflammation than E2, E3, or apoE-KO backgrounds; E4-expressing microglia have higher innate immune reactivity; co-culturing tau-expressing neurons with E4 glia causes more TNF-α secretion and reduced neuronal viability; apoE absence is protective. Human ApoE knock-in tau transgenic mice, immunohistochemistry, ELISA, neuron-glia co-culture, recombinant ApoE treatment Nature High 28959956
2018 APOE4 neurons show increased synapse number and elevated Aβ42 secretion; APOE4 astrocytes display impaired Aβ uptake and cholesterol accumulation; APOE4 microglia-like cells exhibit altered morphologies and reduced Aβ phagocytosis; converting APOE4 to APOE3 in sAD iPSC-derived brain cells attenuates multiple AD-related pathologies. CRISPR/Cas9 isogenic iPSC lines, transcriptional profiling, Aβ secretion/uptake assays, cholesterol measurement, phagocytosis assays Neuron High 29861287
2019 All human ApoE isoforms attenuate classical complement cascade (CCC) activity via high-affinity binding to activated C1q protein (KD ~140-580 pM); C1q-ApoE complexes form in vivo at sites of complement activation including Aβ plaques, choroid plexus, and atherosclerotic arteries; ApoE-deficient mice show oxidized lipid-driven CCC activation and leukocyte infiltration; siRNA against C5 attenuated disease burden. In vitro binding assays (surface plasmon resonance/KD measurement), ApoE-deficient mouse model, siRNA knockdown, immunostaining of human tissues Nature medicine High 30692699
2020 APOE4 leads to blood-brain barrier (BBB) breakdown in the hippocampus and medial temporal lobe independently of Aβ or tau pathology; this is associated with increased activity of the cyclophilin A-MMP9 pathway; CSF levels of soluble PDGFRβ (pericyte injury biomarker) predicted future cognitive decline in APOE4 carriers. Dynamic contrast-enhanced MRI for BBB permeability, CSF biomarkers (PDGFRβ, cyclophilin A, MMP9), PET amyloid/tau imaging in human subjects Nature High 32376954
2016 TREM2 binds directly to APOE (and CLU/APOJ) as identified by unbiased protein microarray screen; binding of apolipoproteins by TREM2 was abolished or reduced by AD-associated TREM2 mutations; TREM2 overexpression enhanced cellular uptake of APOE; Trem2 knockout microglia showed reduced internalization; Aβ bound to APOE is taken up by microglia in a TREM2-dependent fashion. Protein microarray screen, Co-IP, overexpression and KO cellular assays, human macrophages from TREM2 variant carriers Neuron High 27477018
2022 Increased APOE expression in aged human mesenchymal progenitor cells (MPCs) drives cellular senescence; CRISPR-Cas9 deletion of APOE confers resistance to senescence; mechanistically, excess APOE promotes degradation of nuclear lamina proteins and the heterochromatin-associated protein KAP1 via the autophagy-lysosomal pathway, thereby destabilizing heterochromatin. Human cellular aging models, CRISPR-Cas9 KO, Western blot, autophagy-lysosomal pathway inhibitors, chromatin analysis Nature aging High 37117743
2023 Mitochondrial dysfunction (genetic or pharmacological disruption of ETC complexes I, III, or IV, or SLC25A transporters) causes up to 49-fold upregulation of APOE transcript, protein, and secretion as part of an inflammatory gene expression program; this was demonstrated across diverse cell types including iPSC-derived human astrocytes; age- and genotype-dependent decline in complex I preceded APOE increases in 5xFAD mouse brain. Gene editing of ETC components, pharmacological ETC inhibitors, iPSC-derived astrocytes, transcriptomics, ELISA, 5xFAD mouse brain analysis eLife High 37171075
2024 Lipidated ApoE2 (lipApoE2) has impaired LDLR binding compared to lipApoE3/E4, which avoids LDLR recycling defects and decreases uptake of cholesteryl esters (CEs) linked to neurodegeneration; in human neurons, ApoE carrying polyunsaturated fatty acid-CEs causes lipofuscinosis in an allelic series (E4 > E3 > E2); lipofuscin increases lysosomal tau fibril accumulation; intrahippocampal injection of PUFA-CE-lipApoE4 induces lipofuscinosis; the protective Christchurch mutation also reduces LDLR binding, phenocopying ApoE2. iPSC-derived human neurons, LDLR binding assays, lipofuscin quantification, tau fibril uptake assays, intrahippocampal injection in mice, APOE4 mouse brain analysis Cell High 39532095
2008 APP and apoE receptors share extracellular-binding partners (F-spondin, Reelin) that promote their cell surface presence; both APP and apoE receptors are cleaved at the cell surface by alpha-secretase; their processing is regulated by TIMP-3; endothelial APP phosphorylated at Tyr682 associates with Src tyrosine kinase in apoE-/- and AD brains, and APP mediates monocyte adhesion to brain endothelium. Immunohistochemistry, Western blot, co-immunoprecipitation (APP-Src), modified Stamper-Woodruff adhesion assay Molecular neurobiology / Neurobiology of aging Medium 18415033 19058878
2013 The full-length two-domain structure of apoE3 was characterized and shown to support communication between the N-terminal and C-terminal domains; a single amino acid difference (Cys112→Arg) between apoE3 and apoE4 propagates structural changes from the N-terminal domain through to the C-terminal domain. Structural analysis and biophysical characterization of recombinant apoE protein Protein science Medium 24115173

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science (New York, N.Y.) 7642 8346443
1988 Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science (New York, N.Y.) 3529 3283935
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature reviews. Neurology 2574 23296339
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2002 Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. The New England journal of medicine 2327 11844848
2009 Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature genetics 2302 19734902
2017 The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 2172 28930663
2009 Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature genetics 2003 19734903
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 Apolipoprotein E: far more than a lipid transport protein. Annual review of genomics and human genetics 1401 11701639
2007 Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature genetics 1399 17192785
2009 Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proceedings of the National Academy of Sciences of the United States of America 1392 19357304
2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature genetics 1310 18193043
2009 The role of apolipoprotein E in Alzheimer's disease. Neuron 1218 19679070
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature genetics 1130 18193044
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2008 Common variants at 30 loci contribute to polygenic dyslipidemia. Nature genetics 1113 19060906
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2010 Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 992 20460622
2017 ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 964 28959956
2020 APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 943 32376954
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2003 Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proceedings of the National Academy of Sciences of the United States of America 781 14688411
2021 APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet. Neurology 769 33340485
2018 APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron 764 29861287
2016 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 724 27477018
2010 APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals of neurology 724 20186853
2013 ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proceedings of the National Academy of Sciences of the United States of America 452 23620513
1999 Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 286 10366621
2019 ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nature medicine 232 30692699
1977 The initiation sites for RNA transcription in Ad2 DNA. Cell 199 922890
2016 The role of APOE in cerebrovascular dysfunction. Acta neuropathologica 192 26884068
2016 Do the Apoe-/- and Ldlr-/- Mice Yield the Same Insight on Atherogenesis? Arteriosclerosis, thrombosis, and vascular biology 160 27386935
1999 Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 10436064
2017 ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease. Trends in endocrinology and metabolism: TEM 125 28057414
2009 Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. Journal of lipid research 125 19174369
2024 Multifaceted roles of APOE in Alzheimer disease. Nature reviews. Neurology 120 38906999
2020 Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE-/- mice. Theranostics 112 31938053
2001 Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice. Arteriosclerosis, thrombosis, and vascular biology 111 11597927
2020 APOE in the normal brain. Neurobiology of disease 110 31911114
2004 Molecular interactions between apoE and ABCA1: impact on apoE lipidation. Journal of lipid research 108 14754908
2016 Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE- and LDLR-mediated mechanisms. Cardiovascular research 94 26980204
2013 BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/-) mice. PloS one 88 23560095
2022 Destabilizing heterochromatin by APOE mediates senescence. Nature aging 82 37117743
2004 Two apolipoprotein E mimetic peptides, ApoE(130-149) and ApoE(141-155)2, bind to LRP1. Biochemistry 81 15182176
2018 AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/- mice. Biochemical and biophysical research communications 80 29510138
2010 Tanshinone IIA attenuates atherosclerosis in ApoE(-/-) mice through down-regulation of scavenger receptor expression. European journal of pharmacology 77 20854809
2017 AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE-/- mice. Journal of lipid research 72 28611100
2018 ApoE and Neurodegenerative Diseases in Aging. Advances in experimental medicine and biology 70 30232753
2015 Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions. Free radical biology & medicine 68 26169727
2015 IL-9 aggravates the development of atherosclerosis in ApoE-/- mice. Cardiovascular research 64 25784693
1976 Conditional lethal mutants of adenovirus type 2-simian virus 40 hybrids. II. Ad2+ND1 host-range mutants that synthesize fragments of the Ad2+ND1 30K protein. Journal of virology 64 183014
2003 Apolipoprotein E (apoE) isoforms differentially induce nitric oxide production in endothelial cells. FEBS letters 59 12681505
2002 APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss. Molecular psychiatry 59 12192621
2024 Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes. Cell 56 39532095
2023 Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43/HDAC-miRNAs axis in ApoE-/- mice. PloS one 56 36888629
2015 High-methionine diets accelerate atherosclerosis by HHcy-mediated FABP4 gene demethylation pathway via DNMT1 in ApoE(-/-) mice. FEBS letters 54 26606905
2014 Baicalin and geniposide attenuate atherosclerosis involving lipids regulation and immunoregulation in ApoE-/- mice. European journal of pharmacology 54 24991786
1991 Purification and characterization of haloalcohol dehalogenase from Arthrobacter sp. strain AD2. Journal of bacteriology 53 1846134
2017 Human Plasma Thioredoxin-80 Increases With Age and in ApoE-/- Mice Induces Inflammation, Angiogenesis, and Atherosclerosis. Circulation 52 28473446
2000 Complete atherosclerosis regression after human ApoE gene transfer in ApoE-deficient/nude mice. Arteriosclerosis, thrombosis, and vascular biology 52 10669641
2018 Geniposide regulates the miR-101/MKP-1/p38 pathway and alleviates atherosclerosis inflammatory injury in ApoE-/- mice. Immunobiology 51 30630636
2020 Acacetin exerts antioxidant potential against atherosclerosis through Nrf2 pathway in apoE-/- Mice. Journal of cellular and molecular medicine 50 33241629
2005 The interaction of amyloid-beta with ApoE. Sub-cellular biochemistry 48 15709483
2020 Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice. Cardiovascular drugs and therapy 44 32086626
2019 Inflammation inhibition and gut microbiota regulation by TSG to combat atherosclerosis in ApoE-/- mice. Journal of ethnopharmacology 43 31606534
2018 Semaphorin 7A Promotes VEGFA/VEGFR2-Mediated Angiogenesis and Intraplaque Neovascularization in ApoE Mice. Frontiers in physiology 43 30555351
2018 AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE-/- mice. Atherosclerosis 42 29555084
2020 Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX-1 in apoE-/- mice. Experimental and therapeutic medicine 41 33262811
2018 Haplotype analysis of APOE intragenic SNPs. BMC neuroscience 41 29745836
2013 Mercury, APOE, and children's neurodevelopment. Neurotoxicology 41 23603214
2024 Activation of Nrf2 inhibits atherosclerosis in ApoE-/- mice through suppressing endothelial cell inflammation and lipid peroxidation. Redox biology 40 38870781
2020 TSP-1 (Thrombospondin-1) Deficiency Protects ApoE-/- Mice Against Leptin-Induced Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 40 33327743
2012 Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics. International journal of Alzheimer's disease 39 22482072
2017 Asperlin Inhibits LPS-Evoked Foam Cell Formation and Prevents Atherosclerosis in ApoE-/- Mice. Marine drugs 38 29135917
2021 FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE-/- mice atherosclerosis. Laboratory investigation; a journal of technical methods and pathology 37 34725437
2016 Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife. Cortex; a journal devoted to the study of the nervous system and behavior 37 28086184
2011 Npp1 promotes atherosclerosis in ApoE knockout mice. Journal of cellular and molecular medicine 35 21477221
2020 Astragalus Flavone Ameliorates Atherosclerosis and Hepatic Steatosis Via Inhibiting Lipid-Disorder and Inflammation in apoE-/- Mice. Frontiers in pharmacology 34 33381046
2018 6-Gingerol Ameliorates Behavioral Changes and Atherosclerotic Lesions in ApoE-/- Mice Exposed to Chronic Mild Stress. Cardiovascular toxicology 34 29605868
2016 Betulin attenuates atherosclerosis in apoE-/- mice by up-regulating ABCA1 and ABCG1. Acta pharmacologica Sinica 34 27374487
2014 Activation of an innate immune receptor, Nod1, accelerates atherogenesis in Apoe-/- mice. Journal of immunology (Baltimore, Md. : 1950) 34 25488987
2004 The role of viruses and of APOE in dementia. Annals of the New York Academy of Sciences 33 15246985
2017 Celosins inhibit atherosclerosis in ApoE-/- mice and promote autophagy flow. Journal of ethnopharmacology 32 29292046
2013 Concerning the structure of apoE. Protein science : a publication of the Protein Society 32 24115173
2012 Ginkgolide B reduces atherogenesis and vascular inflammation in ApoE(-/-) mice. PloS one 32 22662117
2007 Oxidatively damaged DNA in aging dyslipidemic ApoE-/- and wild-type mice. Mutagenesis 32 17234687
1998 The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Molecular and cellular biology 32 9742120
2020 Protocatechuic Acid Inhibits Vulnerable Atherosclerotic Lesion Progression in Older Apoe-/- Mice. The Journal of nutrition 30 32047914
2019 Metformin Therapy Aggravates Neurodegenerative Processes in ApoE-/- Mice. Journal of Alzheimer's disease : JAD 30 30909226
2023 APOE expression and secretion are modulated by mitochondrial dysfunction. eLife 29 37171075
2019 Tanshinone IIA Promotes Macrophage Cholesterol Efflux and Attenuates Atherosclerosis of apoE-/- Mice by Omentin-1/ABCA1 Pathway. Current pharmaceutical biotechnology 29 30947667
2024 Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference. Alzheimer's & dementia : the journal of the Alzheimer's Association 28 39031528
2022 APOE genetics influence murine gut microbiome. Scientific reports 28 35115575
2016 THSD1 preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE-/- mice. Cardiovascular research 28 26822228
2007 The missing ApoE allele. Annals of human genetics 26 17244188
2010 Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe-/- mice. Atherosclerosis 25 20810111
2023 APOE and immunity: Research highlights. Alzheimer's & dementia : the journal of the Alzheimer's Association 24 36975090
2019 Adipokine Chemerin Stimulates Progression of Atherosclerosis in ApoE-/- Mice. BioMed research international 24 31781638
2018 Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE-/- (Apolipoprotein E Deficient) Mice. Arteriosclerosis, thrombosis, and vascular biology 24 30571174
2017 Berberine ameliorates non-alcoholic steatohepatitis in ApoE-/- mice. Experimental and therapeutic medicine 24 29075339
2011 The neurobiology of APOE in schizophrenia and mood disorders. Frontiers in bioscience (Landmark edition) 24 21196212
2021 Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe-/- mice. Molecular metabolism 23 33991749
1976 Simian virus 40-specific polypeptides in AD2+ ND1- and Ad2+ ND4-infected cells. Journal of virology 23 178903
2021 Antiatherosclerotic effect of dehydrocorydaline on ApoE-/- mice: inhibition of macrophage inflammation. Acta pharmacologica Sinica 22 34552216
2020 Angiopoietin-like protein 8 accelerates atherosclerosis in ApoE-/- mice. Atherosclerosis 22 32739681
2015 The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE-/- mice. Prostaglandins & other lipid mediators 22 26051858
2008 Regulated proteolysis of APP and ApoE receptors. Molecular neurobiology 22 18415033
2023 Contribution of APOE Genetic Variants to Dyslipidemia. Arteriosclerosis, thrombosis, and vascular biology 21 37051929
2021 Naringenin promotes cell autophagy to improve high-fat-diet-induced atherosclerosis in ApoE-/- mice. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 21 33624733
2019 Both gut microbiota and cytokines act to atherosclerosis in ApoE-/- mice. Microbial pathogenesis 21 31682994
2017 Few serum proteins mediate APOE's association with dementia. PloS one 21 28291794
2016 Map3k8 Modulates Monocyte State and Atherogenesis in ApoE-/- Mice. Arteriosclerosis, thrombosis, and vascular biology 21 27856455
2015 Chitosan Oligosaccharides Attenuate Atherosclerosis and Decrease Non-HDL in ApoE-/- Mice. Journal of atherosclerosis and thrombosis 21 25843117
2015 SAP deficiency mitigated atherosclerotic lesions in ApoE(-/-) mice. Atherosclerosis 21 26649902
2007 Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. Schizophrenia research 21 18164902
2022 Genetic disruption of the Gipr in Apoe-/- mice promotes atherosclerosis. Molecular metabolism 20 36055579
2008 Amyloid precursor protein mediates monocyte adhesion in AD tissue and apoE(-)/(-) mice. Neurobiology of aging 20 19058878
2020 Myriocin and d-PDMP ameliorate atherosclerosis in ApoE-/- mice via reducing lipid uptake and vascular inflammation. Clinical science (London, England : 1979) 19 32091078
2021 Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice. Pharmacological research 18 34954030
2020 Atorvastatin promotes bone formation in aged apoE-/- mice through the Sirt1-Runx2 axis. Journal of orthopaedic surgery and research 18 32762716
2020 Downregulation of G3BP2 reduces atherosclerotic lesions in ApoE-/- mice. Atherosclerosis 18 32919187
2016 TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 18 27237075
2016 The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment. Thrombosis and haemostasis 18 27831589
2023 The Impact of Apolipoprotein E (APOE) Epigenetics on Aging and Sporadic Alzheimer's Disease. Biology 17 38132357
2021 Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE-/- mice. Scientific reports 17 33907226
2015 The association of apolipoprotein E (APOE) gene polymorphisms with atherosclerosis susceptibility: a meta-analysis. Minerva cardioangiologica 17 26005211