gene

APOE4

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about APOE4: 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.

1665Connections

30Hypotheses

30Analyses

50Outgoing

50Incoming

19Experiments

20Debates

Summary

APOE4 is a gene implicated in neurodegeneration research. Key relationships include: activates, regulates, associated with. Associated with ALS, ALZHEIMER, ALZHEIMER'S. Connected to 643 entities in the SciDEX knowledge graph.

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🧬 Gene Info

Gene Symbol	APOE4
Aliases	apoe4
Pathways	Stem Cell, PINK1/Parkin axis, ITGB8-TGFβ signaling, Tau Pathology, TAU-LINKED NEURODEGENERATION
Associated Diseases	Aging, Als, Alzheimer, Alzheimer's disease
Known Drugs/Compounds	7C11, aducanumab, donanemab, lecanemab, oxidized unsaturated lipids, rapamycin
Interactions	ABCA1, ABCG1, ACE2, ACETYL-COA, ACHE, Actin
SciDEX Hypotheses	Astrocyte-Selective APOE4 Silencing via Lipid Nano APOE4 Induces Region-Specific Microglial Senescenc APOE4 Structural Correction by Small Molecule Corr
KG Connections	1636 knowledge graph edges
Databases	GeneCards UniProt NCBI Gene HPA STRING

Wiki Pages (10)

Knowledge base pages for this entity

Canonical Page

Pathway Diagram

graph TD
    APOE4["APOE4"] -->|"contributes to"| amyloid_beta_deposits["amyloid beta deposits"]
    APOE4["APOE4"] -.->|"inhibits"| cognition["cognition"]
    APOE4["APOE4"] -->|"causes"| amyloid_pathology["amyloid pathology"]
    APOE4["APOE4"] -->|"associated"| AMYLOID___PLAQUES["AMYLOID-Beta PLAQUES"]
    APOE4["APOE4"] -->|"associated"| TAU_TANGLES["TAU TANGLES"]
    APOE4["APOE4"] -->|"causes"| NEUROINFLAMMATION["NEUROINFLAMMATION"]
    FN1["FN1"] -->|"protects against"| APOE4["APOE4"]
    TREM2["TREM2"] -->|"interacts"| APOE4["APOE4"]
    n_7C11["7C11"] -.->|"inhibits"| APOE4["APOE4"]
    APP["APP"] -.->|"inhibits"| APOE4["APOE4"]
    style APOE4 fill:#4a1a6b,stroke:#4fc3f7,stroke-width:2px,color:#e0e0e0

Outgoing (1283)

Target	Relation	Type	Str
Aging	associated_with	disease	1.00
Alzheimer	expressed_in	disease	1.00
APOE	activates	gene	1.00
APOE	associated_with	gene	1.00
cognitive decline	predicts	process	1.00
intracellular lipid homeostasis	disrupts	process	1.00
Alzheimer	activates	disease	1.00
Als	activates	disease	1.00
neurodegeneration	activates	process	1.00
Alzheimer	associated_with	disease	1.00
Alzheimer's disease	promotes	disease	1.00
Neurodegeneration	activates	disease	1.00
APOE	expressed_in	gene	1.00
Stem Cell	activates	pathway	1.00
late-onset Alzheimer's disease	risk_factor_for	disease	0.98
Blood-Brain Barrier Dysfunction	causes	process	0.95
Glial Lipid Accumulation	promotes	phenotype	0.95
Neurodegeneration	regulates	disease	0.95
Neurodegeneration	promotes	process	0.95
Myelination	associated_with	process	0.95
Tau Pathology	promotes	phenotype	0.95
Late-Onset Alzheimer's Disease	risk_factor_for	disease	0.95
Intracellular Lipid Homeostasis	associated_with	process	0.95
Tau-Mediated Neurodegeneration	associated_with	process	0.95
neurodegenerative microglia response	inhibits	process	0.95
Alzheimer's Disease	risk_factor_for	disease	0.95
Inflammation	regulates	disease	0.95
seizure susceptibility	promotes	phenotype	0.95
Alzheimer'S Disease	risk_factor_for	disease	0.95
PINK1/Parkin axis	inhibits	pathway	0.95
Neuroinflammation	regulates	disease	0.95
cellular lipidome	associated_with	phenotype	0.95
Amyloid-Beta Plaques	promotes	biomarker	0.95
Alzheimer's Disease	risk_factor_for	disease	0.95
Als	associated_with	disease	0.95
Alzheimer	therapeutic_target	disease	0.95
Late-Onset Alzheimer Disease	risk_factor_for	disease	0.95
mitochondrial dysfunction	promotes	phenotype	0.94
ITGB8-TGFβ signaling	activates	pathway	0.93
Lipid Droplet Accumulation	causes	phenotype	0.92
Alzheimer's Disease	drives	disease	0.92
Alzheimer's Disease pathology	contributes_to	phenotype	0.91
NEUTROPHILS	interacts_with	cell_type	0.90
PGK1	downregulates	gene	0.90
ATP1A1	downregulates	gene	0.90
lipid homeostasis	disrupts	process	0.90
Late-Onset Alzheimer's Disease	associated_with	disease	0.90
Glucose intolerance	associated_with	phenotype	0.90
Retinal dysfunction	associated_with	phenotype	0.90
Alzheimer's disease	is_a_risk_factor_for	disease	0.90

Incoming (382)

Source	Relation	Type	Str
h-immunity-c64967ab	relates_to	hypothesis	0.00
AMYLOID	activates	gene	1.00
ALZHEIMER'S DISEASE	activates	gene	1.00
APOE3	activates	gene	1.00
ALZHEIMER	associated_with	gene	1.00
ALZHEIMER	activates	gene	1.00
ALZHEIMER	expressed_in	gene	1.00
ASTROCYTES	activates	gene	1.00
NEURODEGENERATION	activates	gene	1.00
ALZHEIMER'S DISEASE	expressed_in	gene	1.00
ALZHEIMER DISEASE	markers	gene	0.90
h-541d61c3	targets_gene	hypothesis	0.90
FN1	protects_against	gene	0.90
ALZHEIMER'S DISEASE	associated_with	gene	0.90
TREM2	regulates	gene	0.90
ALZHEIMER'S DISEASE	therapeutic_target	gene	0.90
NEURODEGENERATION	regulates	gene	0.90
APOE3	suppresses	protein	0.85
LXR	regulates	protein	0.80
h-541d61c3	targets	hypothesis	0.80
CYP46A1	interacts_with	gene	0.80
C1Q	co_expressed_with	protein	0.80
VEGF	reverses	protein	0.80
MICROGLIA-DERIVED APOE2	modulates	protein	0.80
ALZHEIMER	causes	gene	0.80
TAU PATHOLOGY	activates	gene	0.80
ALZHEIMER	therapeutic_target	gene	0.80
ALZHEIMER	biomarker_for	gene	0.80
ALZHEIMER'S DISEASE	regulates	gene	0.80
TAU	activates	gene	0.80
ALZHEIMER'S DISEASE	biomarker_for	gene	0.80
ALZHEIMER'S DISEASE	causes	gene	0.80
APOE2	protects_against	gene	0.75
MAPT	interacts_with	gene	0.75
ALZHEIMER'S DISEASE	contributes_to	gene	0.70
GAIN	implicated_in	gene	0.70
TREM2	interacts_with	protein	0.70
NEURODEGENERATION	biomarker_for	gene	0.70
PINK1	associated_with	gene	0.70
TAU	implicated_in	gene	0.70
AMYLOID	contributes_to	gene	0.70
INFLAMMATION	regulates	gene	0.70
APOE3	inhibits	gene	0.70
AMYLOID	biomarker_for	gene	0.70
GENES	regulates	gene	0.70
APOE2	associated_with	gene	0.70
ApoE2	modulates	gene	0.70
TAUOPATHY	associated_with	gene	0.70
AMYLOID	associated_with	gene	0.70
ALZHEIMER'S DISEASE	protects_against	gene	0.70

Targeting Hypotheses (30)

Hypotheses where this entity is a therapeutic target

Hypothesis	Score	Disease	Analysis
H1: TREM2 Agonism to Redirect APOE4-Enhanced Microglia from	0.887	neurodegeneration	How does APOE4's beneficial immune funct
Prime Editing Precision Correction of APOE4 to APOE3 in Micr	0.803	neurodegeneration	CRISPR-based therapeutic approaches for
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	-

APOE4 Allosteric Rescue via Small Molecule Chaperones	0.765	neurodegeneration	APOE4 structural biology and therapeutic
APOE4 astrocytes exhibit impaired cholesterol efflux via ABC	0.760	neuroscience	APOE4-driven lipid metabolism dysregulat
Targeted APOE4-to-APOE3 Base Editing Therapy	0.758	neurodegeneration	APOE4 structural biology and therapeutic
APOE4-Selective Lipid Nanoemulsion Therapy	0.742	neurodegeneration	Mechanistic role of APOE in neurodegener
TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid	0.741	Alzheimer's disease	TREM2 agonism vs antagonism in DAM micro
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
TREM2-APOE4 Axis Drives Metabolic Inflexibility in DAM	0.720	Alzheimer's disease	-
APOE4-Specific Microglial Metabolic Rescue	0.710	-	Neuroinflammation and microglial priming
Selective LXRβ agonists restore ABCA1/ABCG1 expression and A	0.710	neuroscience	APOE4-driven lipid metabolism dysregulat
APOE4-driven lysosome-to-ER cholesterol transport failure re	0.690	molecular biology	Does APOE4's reduced lipid-binding direc
Astrocyte Reactivity Heterogeneity with APOE4-Dependent Vuln	0.690	neurodegeneration	Cell type vulnerability debate in Alzhei
TREM2 Agonism to Rescue APOE4-Induced Microglial Dysfunction	0.690	neurodegeneration	APOE4 targeting in neurodegeneration
Astrocyte-Selective APOE4 Silencing via Lipid Nanoparticles	0.682	neurodegeneration	Which cell types show the most significa
Chaperone-Mediated APOE4 Refolding Enhancement	0.680	neurodegeneration	APOE4 structural biology and therapeutic
APOE4 hypolipidation and ABCA1 mistrafficking impair cholest	0.680	molecular biology	Does APOE4's reduced lipid-binding direc
TREM2 R47H variant synergizes with APOE4 to collapse microgl	0.670	neuroscience	APOE4-driven lipid metabolism dysregulat
Astrocyte APOE4-Specific Lipid Metabolism Correction	0.651	neurodegeneration	Cell type vulnerability in Alzheimers Di
Astrocyte Metabolic Reprogramming via APOE4 Correction	0.636	neurodegeneration	Cell type vulnerability in Alzheimer's D
APOE4-microglial complement signaling causes cholinergic-enr	0.630	neurodegeneration	What determines the temporal sequence of
APOE4-Driven Astrocyte Senescence as Primary Target	0.629	-	Senescent cell clearance as neurodegener
APOE4-Targeted Ultrasonic Lipidation Enhancement for Gamma O	0.625	Alzheimer's disease	-
Pharmacological Enhancement of APOE4 Glycosylation	0.622	neurodegeneration	APOE4 structural biology and therapeutic

Mentioning Analyses (30)

Scientific analyses that reference this entity

Experiments (19)

Experimental studies targeting or related to this entity

Experiment	Type	Disease	Score	Feasibility	Model	Status	Est. Cost
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
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 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
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
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
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
AD Combination Therapy Trial: Anti-Aβ + Anti-Tau	clinical	Alzheimer's Disease	0.400	0.50	cell_line	proposed	$180,000
ApoE4 Function in Alzheimer's Disease	validation	Alzheimer's Disease	0.400	0.50	mouse	proposed	$360,000
Biomarker-Guided Sequential Therapy Selection in Alzheimer's Disease	clinical	Alzheimer's Disease	0.400	0.50	human	proposed	$5,460,000
Blood-Based Biomarker Panel for Early AD Detection	clinical	Alzheimer's Disease	0.400	0.50	cell_line	proposed	$220,000
CRISPR Gene Correction Approaches for CBS/PSP	clinical	Parkinson's Disease	0.400	0.50	human	proposed	$6,550,000
Down Syndrome Alzheimer's Disease: Mechanisms and Therapeutic Timing	clinical	Alzheimer's Disease	0.400	0.50	human	proposed	$7,500,000
Sex Differences in Alzheimer's Disease — mechanisms and therapeutic im	clinical	Alzheimer's Disease	0.400	0.50	human	proposed	$7,500,000

Related Papers (20)

Scientific publications cited in analyses involving this entity

Title & PMID	Authors	Journal	Year	Citations
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
An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wid [PMID:38753766]	Huang Q, Chan KY, Wu J, Botticello-Romer	Science	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 in Alzheimer's disease: pathophysiology and therapeutic strategies. [PMID:36348357]	Raulin AC, Doss SV, Trottier ZA, Ikezu T	Mol Neurodegener	2022	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
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
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Mic [PMID:28930663]	Krasemann S, Madore C, Cialic R, Baufeld	Immunity	2017	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
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
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
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
Integrative machine learning approach to risk prediction for dementia and Alzhei [PMID:40864401]	Stern A, Linial M	Geroscience	2026	0

Debates (20)

Multi-agent debates referencing this entity

APOE4

Understanding Entity Pages

Summary

Wiki Pages (10)

ADRD Biomarker Heterogeneity Framework

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

LX1001 Long-Term Follow-up (NCT05400330) - Gene Therapy for APOE4 Homozygote AD

APOE4 and Alzheimer's Disease Risk

ALA-enriched Nutrition for APOE4 Carriers with MCI (NCT07392723)

APOE4 (Apolipoprotein E4)

APOE4 Homozygous Astrocytes

Adenine Base Editing of APOE4 to APOE3 for Alzheimer's Prevention

APOE4 Lipid Homeostasis Modulator for Pre-Symptomatic Alzheimer's Prevention

APOE4 Lipid Metabolism Optimization

Pathway Diagram

Outgoing (1283)

Incoming (382)

Targeting Hypotheses (30)

Mentioning Analyses (30)

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

Multi-modal Biomarker Panel Design for Early AD Detection

Is APOE4's reduced lipid binding pathogenic or a compensatory evolutionary adapt

Does APOE4 drive tau propagation

Lipid metabolism dysregulation in Alzheimer's disease: membrane rafts, gangliosi

Does APOE4 drive tau propagation

Does clusterin exacerbate or protect against neuronal death in neurodegeneration

What specific molecular mechanisms link APOE4 to cholesterol dysregulation in ol

How does APOE4's beneficial immune function reconcile with its established role

What molecular mechanisms underlie the dose-dependent protective effects of the

How does APOE4's beneficial immune function reconcile with its established role

What is the high-resolution structure of the APOE4 hinge region and its role in

Does structural 'normalization' of APOE4 domain interactions actually improve am

Do these mechanistic hypotheses from the SEA-AD Atlas bundle explain layer-speci

Do these mechanistic hypotheses explain layer-specific synaptic vulnerability in

Mechanistic validation of SEA-AD differential expression hypotheses: Complement

Which specific metabolic pathways in APOE4+ microglia are most therapeutically t

How does APOE4 mechanistically increase TDP-43 pathology frequency in Alzheimer'

Do APOE4-driven senescent astrocytes cause neurodegeneration or represent a prot

Epigenetic reprogramming in aging neurons

APOE4-driven lipid metabolism dysregulation in astrocytes and its role in AD

Neuroinflammation and microglial priming in early AD

Neuroinflammation and microglial priming in early Alzheimer's Disease

Neuroinflammation and microglial priming in early Alzheimer's Disease

Tau propagation mechanisms and therapeutic interception points

SEA-AD Single-Cell Analysis: Cell-Type Vulnerability in Alzheimer's Disease

Which cell types show the most significant expression changes for neurodegenerat

Gene expression changes in aging mouse brain predicting neurodegenerative vulner

CRISPR-based therapeutic approaches for neurodegenerative diseases

Immune atlas neuroinflammation analysis in neurodegeneration

Experiments (19)

Related Papers (20)

Debates (20)

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

What are effective therapeutic strategies for targeting APOE4 in Alzheimer's dis

APOE4 is the strongest genetic risk factor for late-onset AD. How APOE4 specific

The debate identified APOE4 astrocytes as potential senescence drivers but did n

The abstract identifies APOE4 association with increased TDP-43 pathology but th

Mechanistic validation of SEA-AD differential expression hypotheses: Complement

Mechanistic validation of SEA-AD differential expression hypotheses: Complement

Do these mechanistic hypotheses explain layer-specific synaptic vulnerability in

Do these mechanistic hypotheses from the SEA-AD Atlas bundle explain layer-speci

Can a multi-modal biomarker panel combining plasma proteins, neuroimaging featur