APOE

Apolipoprotein E

Score: 0.621 Price: $0.62 Medium Druggability Status: active Wiki: APOE

🔴 Alzheimer's Disease 🧠 Neurodegeneration

HYPOTHESES

50

PAPERS

31

KG EDGES

3085

DEBATES

1

3D Protein Structure

🧬 APOE — PDB 3R4L Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.47

Clinical Stage

Phase II

Target Class

Ligand

Safety

0.40

Druggability Analysis

Drug Development0.35

Structural Tractability0.85

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

15

Known Drugs:

4

Approved:

0

In Clinical Trials:

1

Drug Pipeline (4 compounds)

1 Phase II · 3 Preclinical

Druggability Rationale: APOE presents moderate druggability (0.55) despite being a challenging target due to its intrinsically disordered nature and protein-protein interaction mechanism. However, 15 available PDB structures (best resolution 1.4 Å) and successful Phase 2 clinical progress with CN-105 demonstrate that tractable binding pockets exist, particularly for lipid-binding domains and protein interaction interfaces that can be targeted by peptides, small molecules, and biologics.

Mechanism: Protein-protein interaction modulator or lipid metabolism enhancer

Drug Pipeline (4 compounds)

1 Phase II · 3 Preclinical

Known Drugs:

ApoE mimetic peptides (preclinical)

CN-105 (phase_2)

APOE gene therapy vectors (preclinical)

Small molecule APOE modulators (preclinical)

Structural Data:

PDB (15) ✓AlphaFold ✓Cryo-EM ✓

1YA9 2KC3 2L7B 6IWB 6NCN+10 more

UniProt: A0A0S2Z3D5

🧬 3D Protein Structure

🧬 APOE — PDB 3R4L Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

A critical selectivity challenge involves discriminating between APOE isoforms (E2, E3, E4), where E4-selective modulation is therapeutically desired but structurally demanding due to limited sequence divergence. Off-target effects on systemic lipid metabolism and hepatic APOE function must be carefully managed to avoid peripheral toxicity, particularly for brain-penetrant small molecules.

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Clinical Trials (8)

Relevant trials from ClinicalTrials.gov

Active

1

Completed

7

Total Enrollment

484

By Phase

NA: 1 · PHASE1: 3 · PHASE2: 4

Exploring to Remediate Behavioral Disturbances of Spatial Cognition Active Not Recruiting

NA NCT05944601 n=83

Spatial Navigation

Interventions: Virtual and computer-based cognitive rem

Sponsor: Istituto Auxologico Italiano | Started: 2023-03-01

Network-Level Mechanisms for Preclinical Alzheimer's Disease Development Completed

PHASE2 NCT03461861 n=26

APOE 4

Interventions: AGB101 220 mg, Placebo

Sponsor: Medical College of Wisconsin | Started: 2019-04-11

Modulating ApoE Signalling to Reduce Brain Inflammation, deLirium and postopErative Cognitive Dysfunction Completed

PHASE2 NCT03802396 n=203

Postoperative Delirium, Postoperative Cognitive Dysfunction

Interventions: CN-105, Placebo

Sponsor: Miles Berger, MD PhD | Started: 2018-07-15

A Proof of Concept Study to Evaluate CN-105 in ICH Patients Completed

PHASE2 NCT03168581 n=38

Intracerebral Hemorrhage

Interventions: CN-105

Sponsor: AegisCN LLC | Started: 2017-08-28

Evaluation of CN-105 in Subject With Acute Supratentorial Intracerebral Hemorrhage Completed

PHASE2 NCT03711903 n=60

Intracerebral Hemorrhage

Interventions: Acetyl-Valine-Serine-Arginine-Arginine-A, 0.9% Sodium-chloride

Sponsor: National Neuroscience Institute | Started: 2019-03-24

Safety Study of CN-105 Neuroprotective Peptide for Intracerebral Hemorrhage Completed

PHASE1 NCT02670824 n=48

Intracerebral Hemorrhage (ICH)

Interventions: CN-105, Placebo

Sponsor: AegisCN LLC | Started: 2015-12

Mild Alzheimer''s Disease to Assess the of Extended Release Formulation of Rosiglitazone (RSG XR) Completed

PHASE1 NCT00688207 n=14

Alzheimer's Disease

Interventions: Rosiglitazone (Extended Release)

Sponsor: GlaxoSmithKline | Started: 2008-04

A Study to Evaluate the Effect of Bexarotene on Beta-Amyloid and Apolipoprotein E Metabolism in Healthy Subjects Completed

PHASE1 NCT02061878 n=12

Alzheimer's Disease

Interventions: Bexarotene, Placebo

Sponsor: ReXceptor, Inc. | Started: 2014-08

Linked Hypotheses (10)

Prime Editing Precision Correction of APOE4 to APOE3 in Microglia0.850

Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)0.795

Competitive APOE4 Domain Stabilization Peptides0.784

APOE4-Specific Proteolytic Fragment Inhibition Therapy0.777

APOE4 Allosteric Rescue via Small Molecule Chaperones0.765

Targeted APOE4-to-APOE3 Base Editing Therapy0.758

APOE Isoform Expression Across Glial Subtypes0.743

APOE4-Selective Lipid Nanoemulsion Therapy0.742

Interfacial Lipid Mimetics to Disrupt Domain Interaction0.723

Antisense Oligonucleotide-Mediated APOE4 Haploinsufficiency0.720

Linked Experiments (6)

KEEPS Continuation: Long-term effects of menopausal hormone therapy on AD biomarkers0.950

Dairy intake and dementia risk in Malmö Diet and Cancer cohort0.950

APOE4 association with TDP-43 pathology in AD0.750

APOEε4 carriers showed more rapid biomarker changes (decreasing Aβ42:Aβ40, increasing p-tau181, NfL,0.500

Longitudinal plasma biomarker study measuring Aβ42:Aβ40 ratio, p-tau181, NfL, and GFAP at midlife an0.500

Participants carrying the APOE epsilon 4 allele showed more rapid biomarker changes (decreasing Aβ420.500

Scoring Dimensions

Knowledge Graph (20)

associated with (1)

co discussed (14)

OCLN→APOEAPOE→AQP4APOE→MTNR1AAPOE→MTNR1BAPOE→CAV1

▸ Show 9 more

APOE→ABCB1APOE→FCGRTAPOE→CLDN5APOE→DNAJB1APOE→ST6GAL1APOE→FUT8APOE→HSPA1AAPOE→HSP90AA1APOE→FKBP5

expressed in (1)

APOE→MYELOID_CELLS

interacts with (4)

APOE→LRP1LRP1→APOELDLR→APOEAPOE→LDLR

Debate History (1)

Should APOE (Apolipoprotein E) be prioritized as a therapeutic target for neurod2026-04-21