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gene

APOE

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about APOE: its mechanistic relationships (Knowledge Graph edges), hypotheses targeting it, analyses mentioning it, and supporting scientific papers. The interactive graph below shows its immediate neighbors. All content is AI-synthesized from peer-reviewed literature.

4656Connections
30Hypotheses
30Analyses
50Outgoing
50Incoming
17Experiments
20Debates

Summary

Apolipoprotein E (APOE) is the primary cholesterol carrier in the brain, essential for lipid transport, neuronal repair, and synaptic maintenance. The APOE gene has three common alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease, increasing risk 3-15 fold depending on copy number. APOE4 impairs amyloid-beta clearance, promotes neuroinflammation, disrupts blood-brain barrier integrity, and reduces cerebrovascular function. APOE2 is protective, enhancing amyloid clearance and reducing tau pathology. Therapeutic strategies include APOE4 structure correctors, gene therapy to convert APOE4 to APOE3, and anti-APOE4 antibodies.

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AI portrait of APOE

AI-generated illustration · click image to enlarge

Regenerate portrait ↻
🧬 Gene Info
Gene SymbolAPOE
Full NameApolipoprotein E
Chromosome19q13.32
Target ClassLigand
FunctionIt binds to the LDL receptor family to facilitate uptake of lipoprotein particles.
Mechanism of ActionProtein-protein interaction modulator or lipid metabolism enhancer
DruggabilityMedium (0.47)
Clinical StagePhase II
Molecular Weight34 kDa
PathwaysAmyloid, Autophagy, Blood-Brain Barrier, Brain Lipid Metabolism, Cholesterol
GeneCardsAPOE
Human Protein AtlasAPOE
Associated DiseasesAD, Age Of Onset, Aging, alpha-synucleinopathies, Als
Known Drugs/Compoundsatherogenic lipoproteins, Crispr, curcumin, CURCUMIN
InteractionsA2M, ABC7 transporter, ABCA1, abca2, ABCA2, ABCA7
SciDEX TargetView Target Profile (8 clinical trials)
SciDEX HypothesesPrime Editing Precision Correction of APOE4 to APO
Selective APOE4 Degradation via Proteolysis Target
Competitive APOE4 Domain Stabilization Peptides (+22 more)
KG Connections4615 knowledge graph edges
DatabasesGeneCardsUniProtNCBI GeneHPASTRING
🧬 3D Structure Comparison — APOE Experimental (PDB) vs Predicted (AlphaFold) — click to expand

📄 Experimental Structure

2L7B — X-ray / Cryo-EM

🔮 AI Predicted Structure

P02649 — AlphaFold

Left: Experimental structure from RCSB PDB | Right: AI-predicted structure from AlphaFold | Powered by Mol*

Wiki Pages (21)

Knowledge base pages for this entity

Canonical Page

APOE — Apolipoprotein E

gene · 3997 words
→

APOE contributes to Alzheimer's disease by regulating both beta-amyloid deposition

hypothesis · 2704 words
→

APOE contributes to Alzheimer's disease by regulating both beta-amyloid deposition

hypothesis · 2704 words
→

TREM2-APOE Axis in Neurodegeneration

mechanism · 1888 words
→

ABCA1→Cholesterol Efflux→APOE Lipidation→Alzheimer's Disease Causal Chain

mechanism · 1742 words
→

LX1001 Phase 1/2 Trial (NCT03634007) - Gene Therapy for APOE4 Homozygote AD

clinical · 1723 words
→

Pathway Diagram

graph TD
    subgraph Pathology["Pathology"]
        APOE["APOE"] -->|"associated with"| NEURODEGENERATION["NEURODEGENERATION"]
        APOE["APOE"] -->|"associated with"| Atherosclerosis_1["Atherosclerosis"]
        APOE["APOE"] -->|"associated with"| Alzheimer_3["Alzheimer"]
        GENES["GENES"] -->|"associated with"| APOE["APOE"]
        APOE4_4["APOE4"] -->|"associated with"| APOE["APOE"]
        ALZHEIMER_S_DISEASE["ALZHEIMER'S DISEASE"] -->|"associated with"| APOE["APOE"]
    end
    subgraph Therapeutic["Therapeutic"]
        APOE["APOE"] -->|"therapeutic target"| Alzheimer["Alzheimer"]
    end
    subgraph Signaling["Signaling"]
        APOE["APOE"] -.->|"inhibits"| Atherosclerosis["Atherosclerosis"]
        APOE["APOE"] -.->|"inhibits"| Als["Als"]
        APOE["APOE"] -.->|"inhibits"| Cholesterol["Cholesterol"]
        APOE["APOE"] -->|"regulates"| Als_2["Als"]
        APOE["APOE"] -.->|"inhibits"| Inflammation["Inflammation"]
        TREM2["TREM2"] -->|"activates"| APOE["APOE"]
        APOE4["APOE4"] -->|"activates"| APOE["APOE"]
        INFLAMMATION["INFLAMMATION"] -.->|"inhibits"| APOE["APOE"]
    end
    style APOE fill:#4a1a6b,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0,font-weight:bold
    style NEURODEGENERATION fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Alzheimer fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Atherosclerosis fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Als fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Cholesterol fill:#1b5e20,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Atherosclerosis_1 fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Als_2 fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Inflammation fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style Alzheimer_3 fill:#ef5350,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style TREM2 fill:#006494,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style GENES fill:#4a1a6b,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style APOE4 fill:#4a1a6b,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style APOE4_4 fill:#4a1a6b,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style INFLAMMATION fill:#4a1a6b,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0
    style ALZHEIMER_S_DISEASE fill:#4a1a6b,stroke:#4fc3f7,stroke-width:1px,color:#e0e0e0

Outgoing (3278)

TargetRelationTypeStr
benchmark_ot_ad_answer_key:APOEdata_indataset_row0.00
ad_genetic_risk_loci:APOEdata_indataset_row0.00
benchmark_ot_ad_answer_key:APOEdata_indataset_row0.00
TAUassociated_withgene1.00
tauassociated_withprotein1.00

Incoming (1378)

SourceRelationTypeStr
ad_genetic_risk_loci:APOEdata_indataset_row0.00
entities-app-proteininteracts_withwiki0.00
entities-microglia-in-neurodegenerationinteracts_withwiki0.00
benchmark_ot_ad_answer_key:APOEdata_indataset_row0.00
benchmark_ot_ad_answer_key:APOEdata_indataset_row0.00

Targeting Hypotheses (30)

Hypotheses where this entity is a therapeutic target

HypothesisScoreDiseaseAnalysis
H1: TREM2 Agonism to Redirect APOE4-Enhanced Microglia from 0.921 neurodegeneration TREM2 in Alzheimer's Disease: Mechanisms
TREM2-APOE Axis Dissociation for Selective DAM Activation 0.886 neurodegeneration TREM2 agonism vs antagonism in DAM micro
APOE-Dependent Autophagy Restoration 0.877 neurodegeneration Survival Analysis of AD Patient Cohorts:
Prime Editing Precision Correction of APOE4 to APOE3 in Micr 0.827 neurodegeneration CRISPR-based therapeutic approaches for
CLU/APOE Duality in Amyloid Clearance Determines Cell-Type-S 0.811 neurodegeneration What are the cell-type-specific transcri
Selective APOE4 Degradation via Proteolysis Targeting Chimer 0.795 neurodegeneration APOE4 structural biology and therapeutic
Competitive APOE4 Domain Stabilization Peptides 0.784 neurodegeneration APOE4 structural biology and therapeutic
APOE4-Specific Proteolytic Fragment Inhibition Therapy 0.777 Alzheimer's disease -
HDL/apoE Particle Remodeling as a Therapeutic Switch for CAA 0.766 neurodegeneration What molecular mechanisms explain how ap
APOE4 Allosteric Rescue via Small Molecule Chaperones 0.765 neurodegeneration APOE4 structural biology and therapeutic
Targeted APOE4-to-APOE3 Base Editing Therapy 0.758 neurodegeneration APOE4 structural biology and therapeutic
APOE4 astrocytes exhibit impaired cholesterol efflux via ABC 0.758 neuroscience APOE4-driven lipid metabolism dysregulat
TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid 0.757 Alzheimer's disease TREM2 agonism vs antagonism in DAM micro
APOE Isoform Expression Across Glial Subtypes 0.743 Alzheimer's Disease SEA-AD Gene Expression Profiling — Allen
APOE4-Selective Lipid Nanoemulsion Therapy 0.742 neurodegeneration Mechanistic role of APOE in neurodegener
APOE-TREM2 Interaction Modulation 0.741 neurodegeneration Mechanistic role of APOE in neurodegener
Selective LXRβ agonists restore ABCA1/ABCG1 expression and A 0.728 neuroscience APOE4-driven lipid metabolism dysregulat
Proteostasis Enhancement via APOE Chaperone Targeting 0.724 neurodegeneration Mechanistic role of APOE in neurodegener
Interfacial Lipid Mimetics to Disrupt Domain Interaction 0.723 neurodegeneration APOE4 structural biology and therapeutic
LXRβ-Selective Agonism as a Precision Therapeutic for APOE4- 0.721 neurodegeneration What specific molecular mechanisms link
APOE4-driven pericyte injury/senescence is an upstream drive 0.720 neurodegeneration Does pericyte senescence drive BBB break
H3: APOE4 Impairs Cholesterol Trafficking, Triggering Astroc 0.720 neurodegeneration Do APOE4-driven senescent astrocytes cau
Antisense Oligonucleotide-Mediated APOE4 Haploinsufficiency 0.720 neurodegeneration APOE4 targeting in neurodegeneration
APOE Isoform Conversion Therapy 0.718 neurodegeneration Mechanistic role of APOE in neurodegener
APOE4-Specific Microglial Metabolic Rescue 0.710 - Neuroinflammation and microglial priming
APOE4 dual function: beneficial astrocyte anti-inflammatory 0.000 Alzheimer's disease How does APOE4's beneficial immune funct
APOE4-driven loss of neuronal PI(4,5)P2 bridges ganglioside- 0.000 Alzheimer disease Lipid metabolism dysregulation and membr
miR-33 Antisense-Enhanced APOE4 Lipidation as Senolytic Timi 0.000 molecular biology Is APOE4's reduced lipid binding pathoge
LXRα-Selective Agonism to Enhance Hepatic APOE Secretion and 0.000 lipidomics Lipid metabolism dysregulation in Alzhei
CYP2J2-Generated DHA Epoxides Enhance LXRβ-Mediated APOE Lip 0.000 lipidomics Lipid metabolism dysregulation in Alzhei

Mentioning Analyses (30)

Scientific analyses that reference this entity

TREM2 in Alzheimer's Disease: Mechanisms, Therapeutics, and Biomarkers

neurodegeneration | 2026-04-26 | 8 hypotheses Top: 0.990

Does APOE4's reduced lipid-binding directly modulate SREBP2-SCAP complex retenti

molecular biology | 2026-04-24 | 6 hypotheses Top: 0.707

Does Alectinib truly bind C1q directly with high affinity, or is this an experim

molecular biology | 2026-04-21 | 1 hypotheses Top: 0.582

Microglial subtypes in neurodegeneration — friend vs foe

neurodegeneration | 2026-04-17 | 7 hypotheses Top: 0.685

Multi-modal Biomarker Panel Design for Early AD Detection

neurodegeneration | 2026-04-16 | 1 hypotheses Top: 0.559

Experiments (17)

Experimental studies targeting or related to this entity

ExperimentTypeDiseaseScoreFeasibilityModelStatusEst. Cost
KEEPS Continuation: Long-term effects of menopausal hormone therapy on clinical Alzheimer's disease 0.950 0.00 recently menopausal women with proposed N/A
Dairy intake and dementia risk in Malmö Diet and Cancer cohort clinical Alzheimer's disease 0.950 0.00 Swedish community-based adults proposed N/A
GWAS of plasma NfL in East Asian cohort exploratory Alzheimer's disease 0.950 0.00 human patients - East Asian co proposed N/A
GWAS of plasma pTau217 in East Asian cohort exploratory Alzheimer's disease 0.950 0.00 human patients - East Asian co proposed N/A
GWAS of plasma pTau181 in East Asian cohort exploratory Alzheimer's disease 0.950 0.00 human patients - East Asian co proposed N/A
GWAS of plasma GFAP in East Asian cohort exploratory Alzheimer's disease 0.950 0.00 human patients - East Asian co proposed N/A
iPSC-NPC effects on astrocytes in vitro ICH model exploratory intracerebral hemorrhage 0.900 0.00 in vitro ICH cell culture mode completed N/A
GWAS of composite biomarker score exploratory Alzheimer's disease 0.900 0.00 human patients - East Asian co proposed N/A
RBG treatment in ApoE-/- atherosclerosis mouse model validation atherosclerosis 0.900 0.00 ApoE-/- mice proposed N/A
Reelin glycoprotein treatment rescue experiment validation Alzheimer's disease 0.900 0.00 mice proposed N/A
ABCA1 rs2230806 polymorphism association with dementia risk in hyperli exploratory dementia, Alzheimer's disease 0.900 0.00 human patients proposed N/A
AMPK knockdown validation experiment exploratory intracerebral hemorrhage 0.880 0.00 astrocyte cell culture proposed N/A
P2RY12-MTOR pathway interaction in VSMCs exploratory atherosclerosis 0.850 0.00 cultured VSMCs proposed N/A
iPSC-NPC transplantation in ICH animal model validation intracerebral hemorrhage 0.850 0.00 animal ICH model proposed N/A
APOE4 association with TDP-43 pathology in AD exploratory Alzheimer's disease 0.750 0.00 human patients proposed N/A
s:** - Biochemical binding assays measuring PROTAC selectivity for APO falsification Neurodegeneration 0.400 0.50 cell_line proposed $100,000
Why Does Amyloid Removal Only Slow Decline 27%? — Mechanistic investig clinical Alzheimer's Disease 0.400 0.50 human proposed $7,100,000

Related Papers (20)

Scientific publications cited in analyses involving this entity

Title & PMIDAuthorsJournalYearCitations
Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of [PMID:30335591] Rusmini P, Cortese K, Crippa V, Cristofa Autophagy 2019 2
Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegenerat [PMID:37995685] Litvinchuk A, Suh JH, Guo JL, Lin K, Dav Neuron 2024 1
The cell biology of APOE in the brain. [PMID:37805344] Windham IA, Cohen S Trends Cell Biol 2024 1
The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegene [PMID:37957317] Maxine R Nelson, Peng Liu, Ayushi Agrawa Nature neuroscience 2023 1
APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therape [PMID:33340485] Serrano-Pozo A, Das S, Hyman BT Lancet Neurol 2021 1
Lysosome-targeting chimaeras for degradation of extracellular proteins. [PMID:32728216] Banik SM, Pedram K, Wisnovsky S, Ahn G, Nature 2020 1
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2- [PMID:31932797] Zhou Y, Song WM, Andhey PS, Swain A, Lev Nat Med 2020 1
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. [PMID:31564456] Long JM, Holtzman DM Cell 2019 1
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. [PMID:31367008] Yamazaki Y, Zhao N, Caulfield TR, Liu CC Nat Rev Neurol 2019 1
Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associate [PMID:41905188] Cetindag AC, Schipke CG, Esselmann H, Kr The journal of prevention of A 2026 0
Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, a [PMID:41858499] ["Barger S", "Moerman-Herzog A"] Frontiers in molecular neurosc 2026 0
Replating Induces mTOR-Dependent Rescue of Protein Synthesis in Charcot-Marie-To [PMID:41876253] Koenig J, McGuire A, Homedan Y, Alberhas eNeuro 2026 0
ASS1 Promotes Atherosclerotic Inflammation Through the NLRP3/IL-33/ST2 Axis in O [PMID:41914296] Wu S, Han F, Qiao Z, Yuan S, Bian X, Zha Frontiers in bioscience (Landm 2026 0
S-equol promotes ferroptosis in triple negative breast cancer by coordinating NC [PMID:41925800] Ni F, Huang Z, Cui Y, Huang P, Xue Z, Hu Molecular and cellular biochem 2026 0
Modulating LRP1 Pathways in Alzheimer's Disease: Mechanistic Insights and Emergi [PMID:41772271] Mushtaq T, Hameed H, Khan MA, Tariq U, H Molecular neurobiology 2026 0
CRISPR-based correction of apolipoprotein E4 in Alzheimer's disease: Therapeutic [PMID:41812941] ["Wang M", "Niu D", "Zhang Q", "Tang Y", International journal of biolo 2026 0
Multimodal biomarker AI techniques for early neurocognitive disorder diagnosis: [PMID:41921464] Catino F, Castellana F, Zupo R, Giannocc Artificial intelligence in med 2026 0
Neuroprotective Effects of Berberine Chloride Against the Aluminium Chloride-Ind [PMID:40014257] Uvarajan D, Gnanarajan R, Karuppusamy PA Mol Biotechnol 2026 0
Perioperative polygenic and APOE-based genetic risk assessment for neurocognitiv [PMID:40562635] Thedim M, Hu J, Maher M, Wiener-Kronish Br J Anaesth 2026 0
Increased genetic protection against Alzheimer's disease in centenarians. [PMID:40615639] Bae H, Song Z, Ali A, Sasaki T, Tesi N e Geroscience 2026 0

Debates (20)

Multi-agent debates referencing this entity

Hypothesis debate: Metabolic Reprogramming to Reverse Senescence

closed · Rounds: 4 · Score: 0.00 · 2026-04-27

Hypothesis debate: Closed-loop transcranial focused ultrasound with 40Hz gamma e

closed · Rounds: 4 · Score: 0.00 · 2026-04-27

Hypothesis debate: Closed-loop transcranial focused ultrasound with 40Hz gamma e

closed · Rounds: 4 · Score: 0.00 · 2026-04-27

Should '40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Sele

active · Rounds: 4 · Score: 0.52 · 2026-04-27

Should 'ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes Drives White Matt

active · Rounds: 4 · Score: 0.72 · 2026-04-27

Hypothesis debate: GluN2B-Mediated Thalamocortical Control of Glymphatic Tau Cle

closed · Rounds: 4 · Score: 0.00 · 2026-04-27

Hypothesis debate: Closed-loop focused ultrasound targeting EC-II SST interneuro

closed · Rounds: 4 · Score: 0.00 · 2026-04-27

Hypothesis debate: PLCG2 Allosteric Modulation as a Precision Therapeutic for TR

closed · Rounds: 4 · Score: 0.50 · 2026-04-26

Hypothesis debate: PLCG2 Allosteric Modulation as a Precision Therapeutic for TR

closed · Rounds: 4 · Score: 0.50 · 2026-04-26

Hypothesis debate: Closed-loop optogenetic targeting PV interneurons to restore

closed · Rounds: 4 · Score: 0.50 · 2026-04-26

Related Research

Hypotheses and analyses mentioning APOE in their description or question text

Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)

Score: 0.795 · neurodegeneration · 2026-04-02

## Mechanistic Overview Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs) starts from the claim t

Competitive APOE4 Domain Stabilization Peptides

Score: 0.784 · neurodegeneration · 2026-04-02

## Mechanistic Overview Competitive APOE4 Domain Stabilization Peptides starts from the claim that modulating APOE withi

HDL/apoE Particle Remodeling as a Therapeutic Switch for CAA Prevention

Score: 0.766 · neurodegeneration · 2026-04-15

## Mechanistic Overview HDL/apoE Particle Remodeling as a Therapeutic Switch for CAA Prevention starts from the claim th

APOE4 Allosteric Rescue via Small Molecule Chaperones

Score: 0.765 · neurodegeneration · 2026-04-02

## Mechanistic Overview APOE4 Allosteric Rescue via Small Molecule Chaperones starts from the claim that modulating APOE

Targeted APOE4-to-APOE3 Base Editing Therapy

Score: 0.758 · neurodegeneration · 2026-04-02

**Molecular Mechanism and Rationale** The apolipoprotein E4 (APOE4) variant represents the most significant genetic ris

APOE4 astrocytes exhibit impaired cholesterol efflux via ABCA1/ABCG1 transporter

Score: 0.758 · neuroscience · 2026-04-22

## Mechanistic Overview APOE4 astrocytes exhibit impaired cholesterol efflux via ABCA1/ABCG1 transporters, driving intra

TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid Sensing and Clearanc

Score: 0.757 · Alzheimer's disease · 2026-04-04

## Mechanistic Overview TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid Sensing and Clearance Deficits start

APOE Isoform Expression Across Glial Subtypes

Score: 0.743 · Alzheimer's Disease · 2026-04-02

## Mechanistic Overview APOE Isoform Expression Across Glial Subtypes starts from the claim that modulating APOE within

APOE4-Selective Lipid Nanoemulsion Therapy

Score: 0.742 · neurodegeneration · 2026-04-02

## Mechanistic Overview APOE4-Selective Lipid Nanoemulsion Therapy starts from the claim that modulating APOE within the

APOE-TREM2 Interaction Modulation

Score: 0.741 · neurodegeneration · 2026-04-02

## Mechanistic Overview APOE-TREM2 Interaction Modulation starts from the claim that modulating TREM2 within the disease

Selective LXRβ agonists restore ABCA1/ABCG1 expression and APOE lipidation in AP

Score: 0.728 · neuroscience · 2026-04-22

**Molecular Mechanism and Rationale** The molecular basis for selective liver X receptor beta (LXRβ/NR1H2) agonism in A

Proteostasis Enhancement via APOE Chaperone Targeting

Score: 0.724 · neurodegeneration · 2026-04-02

## Mechanistic Overview Proteostasis Enhancement via APOE Chaperone Targeting starts from the claim that modulating HSPA

Interfacial Lipid Mimetics to Disrupt Domain Interaction

Score: 0.723 · neurodegeneration · 2026-04-02

## Mechanistic Overview Interfacial Lipid Mimetics to Disrupt Domain Interaction starts from the claim that modulating A

LXRβ-Selective Agonism as a Precision Therapeutic for APOE4-Driven Myelin Defici

Score: 0.721 · neurodegeneration · 2026-04-14

## Mechanistic Overview LXRβ-Selective Agonism as a Precision Therapeutic for APOE4-Driven Myelin Deficits starts from t
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