APOE Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human APOE — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene APOE, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene APOE, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene APOE protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene APOE protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene APOE, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene APOE, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene APOE, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene APOE protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene APOE, summarize transcription factor regulatory data. If APOE is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate APOE — names with evidence type (ChIP-seq / predicted / experimentally validated) If APOE is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene APOE protein as a drug target, summarize pharmacology data. If APOE is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If APOE is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene APOE, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene APOE, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in APOE: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
APOE (apolipoprotein E, chromosome 19q13.32) encodes a secreted lipoprotein that mediates lipid transport and clearance across multiple tissues, and stands as one of the most pleiotropic disease-risk genes in the human genome. Its single most important clinical significance is as the strongest known common genetic risk factor for late-onset Alzheimer’s disease, with GWAS p-values reaching 3e-105, alongside equally striking associations with LDL cholesterol (p=3.01e-322), total cholesterol (p=8e-315), and HDL cholesterol (p=1e-142). The protein is ubiquitously expressed (Bgee average score 88.4 across 287 conditions), with highest levels in the adrenal cortex and liver, and prominent expression in CNS glial cells and macrophages — cell types central to neuroinflammation and amyloid clearance. Structurally, it is exceptionally well-characterised, with 29 experimental PDB structures resolved. Despite its outsized disease relevance, APOE is not currently a direct drug target: only 8 non-specific DrugBank interactions are recorded and zero ChEMBL agents are indexed against it, with pharmacological effort instead directed at modulating downstream pathways.
APOE — Reference
Cross-database identifier and functional mapping reference for APOE.
Gene identifiers
- HGNC ID: HGNC:613
- Approved symbol: APOE
- Ensembl gene ID: ENSG00000130203
- NCBI Entrez Gene ID: 348
- OMIM ID: 107741
- Genomic location (GRCh38):
- Chromosome: 19
- Start position: 44,903,787
- End position: 44,909,396
- Strand: +
Transcript identifiers
Ensembl transcripts (32 total)
| ENST ID | Biotype |
|---|---|
| ENST00000252486 | protein_coding |
| ENST00000425718 | protein_coding |
| ENST00000434152 | protein_coding |
| ENST00000446996 | protein_coding |
| ENST00000485628 | retained_intron |
| ENST00000864817 | protein_coding |
| ENST00000864820 | protein_coding |
| ENST00000864822 | protein_coding |
| ENST00000864824 | protein_coding |
| ENST00000864826 | protein_coding |
| ENST00000864828 | protein_coding |
| ENST00000864829 | protein_coding |
| ENST00000864830 | protein_coding |
| ENST00000864831 | protein_coding |
| ENST00000864832 | protein_coding |
| ENST00000864833 | protein_coding |
| ENST00000864834 | protein_coding |
| ENST00000864835 | protein_coding |
| ENST00000864836 | protein_coding |
| ENST00000864837 | protein_coding |
| ENST00000864838 | protein_coding |
| ENST00000864839 | protein_coding |
| ENST00000864840 | protein_coding |
| ENST00000864841 | protein_coding |
| ENST00000864842 | protein_coding |
| ENST00000864843 | protein_coding |
| ENST00000864844 | protein_coding |
| ENST00000864845 | protein_coding |
| ENST00000864846 | protein_coding |
| ENST00000864847 | protein_coding |
| ENST00000864848 | protein_coding |
| ENST00000864849 | protein_coding |
31 protein_coding, 1 retained_intron
RefSeq mRNA accessions (5 total)
| NM_ | Status | MANE Select |
|---|---|---|
| NM_000041 | REVIEWED | ✓ Yes |
| NM_001302688 | REVIEWED | No |
| NM_001302689 | REVIEWED | No |
| NM_001302690 | REVIEWED | No |
| NM_001302691 | REVIEWED | No |
CCDS ID
- CCDS12647
MANE Select transcript exons: ENST00000252486
| Exon ID | Start | End | Biotype |
|---|---|---|---|
| ENSE00001048576 | 44905796 | 44905841 | 5’ UTR exon |
| ENSE00003577086 | 44906602 | 44906667 | CDS exon |
| ENSE00000893952 | 44907760 | 44907952 | CDS exon |
| ENSE00000893954 | 44908533 | 44909393 | CDS + 3’ UTR exon |
Total exon count: 4
Protein identifiers
UniProt accessions
- P02649 ✓ Reviewed (canonical)
- A0A0S2Z3D5 (unreviewed)
- E7ERP7 (unreviewed)
- E9PEV4 (unreviewed)
- H0Y7L5 (unreviewed)
RefSeq protein (NP_ accessions)
- NP_000032 (MANE select, canonical)
- NP_001257610
- NP_001257611
- NP_001257612
- NP_001257613
- NP_001289617
- NP_001289618
- NP_001289619
- NP_001289620
- NP_001292748
- NP_001292772
- NP_001292773
- NP_033826
- NP_620183
- XP_030097875 (predicted protein)
Protein domains and families
| ID | Name | Type | Database |
|---|---|---|---|
| IPR000074 | Apolipoprotein A/E | Family | InterPro |
| IPR050163 | Apolipoprotein A1/A4/E | Family | InterPro |
| PF01442 | Apolipoprotein | Domain | Pfam |
Antibody availability
No antibody database entries detected via biobtree mapping. Cross-references indicate associations with Human Protein Atlas (HPA) and other antibody resources (HPA count: 1), but specific antibody products/clones are not listed in biobtree.
Structure
Experimental Structures (PDB)
Total: 29 structures
| PDB ID | Experimental Method | Resolution (Å) |
|---|---|---|
| 1B68 | X-ray diffraction | 2.0 |
| 1BZ4 | X-ray diffraction | 1.85 |
| 1EA8 | X-ray diffraction | 1.95 |
| 1GS9 | X-ray diffraction | 1.7 |
| 1H7I | X-ray diffraction | 1.9 |
| 1LE2 | X-ray diffraction | 3.0 |
| 1LE4 | X-ray diffraction | 2.5 |
| 1LPE | X-ray diffraction | 2.25 |
| 1NFN | X-ray diffraction | 1.8 |
| 1NFO | X-ray diffraction | 2.0 |
| 1OEF | Solution NMR | — |
| 1OEG | Solution NMR | — |
| 1OR2 | X-ray diffraction | 2.5 |
| 1OR3 | X-ray diffraction | 1.73 |
| 2KC3 | Solution NMR | — |
| 2KNY | Solution NMR | — |
| 2L7B | Solution NMR | — |
| 6IWB | X-ray diffraction | 2.5 |
| 6NCN | X-ray diffraction | 1.82 |
| 6NCO | X-ray diffraction | 1.707 |
| 6V7M | X-ray diffraction | 2.0 |
| 7FCR | X-ray diffraction | 1.4 |
| 7FCS | X-ray diffraction | 1.6 |
| 7UVJ | X-ray diffraction | 1.99 |
| 8AX8 | X-ray diffraction | 1.551 |
| 8AX9 | X-ray diffraction | 1.549 |
| 8CDY | X-ray diffraction | 1.9 |
| 8CE0 | X-ray diffraction | 1.75 |
| 8GRX | Cryo-EM | 3.0 |
Method breakdown: 24 X-ray diffraction, 4 Solution NMR, 1 Cryo-EM
Predicted Structures (AlphaFold)
- Model ID: P02649
- pLDDT (Global Metric): 76.13
- Fraction High Confidence (pLDDT >90): 33%
Cross-species orthologs
| Organism | Gene ID | Gene Symbol |
|---|---|---|
| Mouse (Mus musculus) | 11816 | Apoe |
| Rat (Rattus norvegicus) | 25728 | Apoe |
| Zebrafish (Danio rerio) | 30314; 553587 | apoeb; apoea |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Summary
Total variants: 263
Classification breakdown (sample from 100 retrieved):
| Classification | Count |
|---|---|
| Pathogenic | ~13 |
| Likely Pathogenic | ~6 |
| VUS | ~20 |
| Likely Benign | ~35 |
| Benign | ~10 |
| Other (drug response, conflicting) | ~16 |
Top Pathogenic & Likely Pathogenic Variants (ClinVar)
| Variant ID | HGVS Notation | Classification | Condition/Note |
|---|---|---|---|
| 17849 | NM_000041.4(APOE):c.61G>A (p.Glu21Lys) | Pathogenic | Familial lipoprotein lipase deficiency |
| 17852 | NM_000041.4(APOE):c.237-2A>G | Pathogenic | Splicing defect |
| 17857 | NM_000041.4(APOE):c.490A>G (p.Lys164Glu) | Pathogenic | Lipoprotein disorder |
| 17858 | NM_000041.4(APOE):c.490A>C (p.Lys164Gln) | Pathogenic | Lipoprotein disorder |
| 17859 | NM_000041.4(APOE):c.736C>T (p.Arg246Cys) | Pathogenic | Type III hyperlipoproteinemia |
| 17861 | NM_000041.4(APOE):c.146del (p.Gly49fs) | Pathogenic | Frameshift |
| 17874 | NM_000041.4(APOE):c.455G>A (p.Arg152Gln) | Pathogenic | Lipoprotein disorder |
| 17875 | NM_000041.4(APOE):c.875G>A (p.Arg292His) | Pathogenic | Alzheimer disease risk |
| 17879 | NM_000041.4(APOE):c.488G>C (p.Arg163Pro) | Pathogenic | Lipoprotein disorder |
| 17880 | NM_000041.4(APOE):c.127C>T (p.Arg43Cys) | Pathogenic/Likely | Lipoprotein disorder |
| 126456 | NM_000041.4(APOE):c.497TCC[1] (p.Leu167del) | Pathogenic | Microsatellite deletion |
| 1077013 | NM_000041.4(APOE):c.494G>C (p.Arg165Pro) | Likely Pathogenic | Unknown |
| 17862 | NM_000041.4(APOE):c.683G>A (p.Trp228Ter) | Likely Pathogenic | Nonsense mutation |
| 17865 | NM_000041.4(APOE):c.488G>A (p.Arg163His) | Likely Pathogenic | Lipoprotein disorder |
| 1341575 | NM_000041.4(APOE):c.548G>C (p.Gly183Ala) | Likely Pathogenic | Unknown |
| 17850 | NM_000041.4(APOE):c.460C>A (p.Arg154Ser) | Likely Pathogenic | Lipoprotein disorder |
AlphaMissense Pathogenicity Predictions
Total predictions: ~337
Likely Pathogenic variants (top 30):
| Variant | Protein Change | am_pathogenicity | Effect |
|---|---|---|---|
| 19:44906637:T:A | W5R | 0.869 | Trp to Arg (charge reversal) |
| 19:44906637:T:C | W5R | 0.869 | Trp to Arg (charge reversal) |
| 19:44906641:C:A | A6D | 0.783 | Ala to Asp (charge introduction) |
| 19:44906644:C:A | A7E | 0.836 | Ala to Glu (charge introduction) |
| 19:44906650:T:G | L9R | 0.692 | Leu to Arg (hydrophobic→charged) |
| 19:44906650:T:A | L9Q | 0.567 | Leu to Gln (hydrophobic→polar) |
| 19:44906653:T:A | V10D | 0.827 | Val to Asp (charge introduction) |
| 19:44906656:C:A | T11K | 0.790 | Thr to Lys (charge introduction) |
| 19:44906656:C:G | T11R | 0.690 | Thr to Arg (charge introduction) |
| 19:44906665:C:A | A14E | 0.633 | Ala to Glu (charge introduction) |
| 19:44906667:G:A | G15R | 0.730 | Gly to Arg (rigidity→charged) |
| 19:44906667:G:C | G15R | 0.730 | Gly to Arg (rigidity→charged) |
| 19:44907760:G:A | G15E | 0.728 | Gly to Glu (rigidity→charged) |
| 19:44907762:T:C | C16R | 0.684 | Cys to Arg (polar→charged) |
| 19:44907764:C:G | C16W | 0.575 | Cys to Trp (polar→hydrophobic) |
SpliceAI Predictions
Total predictions: 450
Highest-impact splice variants (sample of high-confidence predictions):
| Position | Variant | Effect Type | Score |
|---|---|---|---|
| 19:44905816 | TG:T | donor_gain | 0.95 |
| 19:44905821 | G:GT | donor_gain | 0.98 |
| 19:44905838 | GCCG:G | donor_gain | 0.99 |
| 19:44905839 | CCGG:C | donor_loss | 0.97 |
| 19:44905840 | CGGTG:C | donor_loss | 0.97 |
| 19:44905841 | GGT:G | donor_loss | 0.97 |
| 19:44905842 | G:GG | donor_gain | 0.98 |
| 19:44905843 | T:A | donor_loss | 0.97 |
| 19:44905844 | GA:G | donor_loss | 0.97 |
| 19:44905845 | A:AC | donor_loss | 0.95 |
| 19:44906866 | GGGA:G | donor_gain | 0.91 |
Pathways & Gene Ontology
Reactome Pathways
Total: 12 pathways
| ID | Pathway Name |
|---|---|
| R-HSA-1251985 | Nuclear signaling by ERBB4 |
| R-HSA-3000480 | Scavenging by Class A Receptors |
| R-HSA-381426 | Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) |
| R-HSA-8864260 | Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors |
| R-HSA-8957275 | Post-translational protein phosphorylation |
| R-HSA-8963888 | Chylomicron assembly |
| R-HSA-8963901 | Chylomicron remodeling |
| R-HSA-8964026 | Chylomicron clearance |
| R-HSA-8964058 | HDL remodeling |
| R-HSA-9029569 | NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux |
| R-HSA-975634 | Retinoid metabolism and transport |
| R-HSA-977225 | Amyloid fiber formation |
MSigDB Gene Sets
Total: 100+ gene sets (showing first 100)
Key functional annotations include:
- Lipoprotein metabolism and transport (cholesterol efflux, HDL remodeling, VLDL/LDL clearance)
- Neuronal function (dendritic spine development, synaptic transmission, long-term memory)
- Lipid metabolism (triglyceride homeostasis, sterol homeostasis, fatty acid transport)
- Inflammatory response and coagulation regulation
- Amyloid precursor protein metabolism
Gene Ontology Annotations
Biological Process
Total: ~92 terms
Top 20:
- GO:0033344 | Cholesterol efflux
- GO:0042982 | Amyloid precursor protein metabolic process
- GO:0042159 | Lipoprotein catabolic process
- GO:0042158 | Lipoprotein biosynthetic process
- GO:0034380 | High-density lipoprotein particle assembly
- GO:0034374 | Low-density lipoprotein particle remodeling
- GO:0034375 | High-density lipoprotein particle remodeling
- GO:0034382 | Chylomicron remnant clearance
- GO:0034384 | High-density lipoprotein particle clearance
- GO:0034447 | Very-low-density lipoprotein particle clearance
- GO:0043691 | Reverse cholesterol transport
- GO:0071830 | Triglyceride-rich lipoprotein particle clearance
- GO:0010875 | Positive regulation of cholesterol efflux
- GO:0042632 | Cholesterol homeostasis
- GO:0031175 | Neuron projection development
- GO:0008203 | Cholesterol metabolic process
- GO:0006641 | Triglyceride metabolic process
- GO:0071402 | Cellular response to lipoprotein particle stimulus
- GO:1900223 | Positive regulation of amyloid-beta clearance
- GO:0045807 | Positive regulation of endocytosis
Molecular Function
Total: ~22 terms
Top 20:
- GO:0071813 | Lipoprotein particle binding
- GO:0005319 | Lipid transporter activity
- GO:0008289 | Lipid binding
- GO:0001540 | Amyloid-beta binding
- GO:0048156 | Tau protein binding
- GO:0050750 | Low-density lipoprotein particle receptor binding
- GO:0070326 | Very-low-density lipoprotein particle receptor binding
- GO:0005543 | Phospholipid binding
- GO:0043395 | Heparan sulfate proteoglycan binding
- GO:0005102 | Signaling receptor binding
- GO:0046983 | Protein dimerization activity
- GO:0042803 | Protein homodimerization activity
- GO:0042802 | Identical protein binding
- GO:0019899 | Enzyme binding
- GO:0044877 | Protein-containing complex binding
- GO:0008201 | Heparin binding
- GO:0016209 | Antioxidant activity
- GO:0005198 | Structural molecule activity
- GO:0060228 | Phosphatidylcholine-sterol O-acyltransferase activator activity
- GO:0120020 | Cholesterol transfer activity
Cellular Component
Total: ~27 terms
Top 20:
- GO:1990777 | Lipoprotein particle
- GO:0034364 | High-density lipoprotein particle
- GO:0034362 | Low-density lipoprotein particle
- GO:0034361 | Very-low-density lipoprotein particle
- GO:0034363 | Intermediate-density lipoprotein particle
- GO:0034360 | Chylomicron remnant
- GO:0042627 | Chylomicron
- GO:0034365 | Discoidal high-density lipoprotein particle
- GO:0070062 | Extracellular exosome
- GO:1903561 | Extracellular vesicle
- GO:0005576 | Extracellular region
- GO:0005615 | Extracellular space
- GO:0031012 | Extracellular matrix
- GO:0005886 | Plasma membrane
- GO:0005783 | Endoplasmic reticulum
- GO:0005794 | Golgi apparatus
- GO:0005737 | Cytoplasm
- GO:0005634 | Nucleus
- GO:0043025 | Neuronal cell body
- GO:0030425 | Dendrite
Protein interactions & networks
Protein-Protein Interactions
Total interaction count:
- STRING: ~6,284 interactions
- IntAct: 293 interactions
- BioGRID: 216 interactions
TOP 30 highest-confidence interacting proteins (STRING database):
| Rank | Protein ID | Protein Name | STRING Interactions |
|---|---|---|---|
| 1 | P02768 | Albumin | 10,898 |
| 2 | P05067 | Amyloid-beta precursor protein (APP) | 7,062 |
| 3 | P16070 | CD44 antigen | 6,319 |
| 4 | P04114 | Apolipoprotein B-100 (APOB) | 4,882 |
| 5 | P02766 | Transthyretin (TTR) | 4,128 |
| 6 | P10909 | Clusterin (CLU) | 3,594 |
| 7 | O95477 | Phospholipid-transporting ATPase ABCA1 | 3,322 |
| 8 | P02647 | Apolipoprotein A-I (APOA1) | 3,172 |
| 9 | P01141 | Angiotensinogen | 2,864 |
| 10 | P05090 | Apolipoprotein D (APOD) | 2,648 |
| 11 | P01023 | Alpha-2-macroglobulin (A2M) | 2,534 |
| 12 | P98164 | Low-density lipoprotein receptor-related protein 2 (LRP2/Megalin) | 2,184 |
| 13 | Q07954 | Low-density lipoprotein receptor-related protein 1 (LRP1) | 2,292 |
| 14 | Q92673 | Sortilin-related receptor (SORL1) | 2,036 |
| 15 | Q9NZC2 | Triggering receptor expressed on myeloid cells 2 (TREM2) | 2,320 |
| 16 | P98155 | Very low-density lipoprotein receptor (VLDLR) | 1,719 |
| 17 | P02656 | Apolipoprotein C-III (APOC3) | 1,802 |
| 18 | P02652 | Apolipoprotein A-II (APOA2) | 1,700 |
| 19 | P06727 | Apolipoprotein A-IV (APOA4) | 1,212 |
| 20 | P02743 | Serum amyloid P-component (APCS) | 1,191 |
| 21 | P08603 | Complement factor H (CFH) | 1,508 |
| 22 | Q14114 | Low-density lipoprotein receptor-related protein 8 (LRP8/APOER2) | 1,510 |
| 23 | P02655 | Apolipoprotein C-II (APOC2) | 1,118 |
| 24 | P02654 | Apolipoprotein C-I (APOC1) | 1,304 |
| 25 | P10636 | Microtubule-associated protein tau (MAPT) | 5,558 |
Protein Structural/Embedding Similarity
ESM2 embedding similarity: 157 similar proteins identified Top matches include APOE orthologs and variant isoforms from multiple organisms (P02650, P05770, P0DKU9-P0DKY2, and other evolutionary variants)
DIAMOND sequence similarity: 79 homologous proteins identified Top sequence homologs include:
- APOE variants (P02650, P08226)
- Apolipoprotein orthologs from mammalian species (bovine, ovine, rodent)
- Other lipid-binding proteins with conserved domains
Key Functional Networks
Lipoprotein metabolism pathway: APOE interacts with all major apolipoproteins (ApoA-I, ApoA-II, ApoA-IV, ApoB-100, ApoC-I/II/III, ApoD), lipid transporters (ABCA1), and lipoprotein receptors (LDL-R superfamily: LRP1, LRP2, LRP8, VLDLR)
Amyloid-β pathway: Direct interactions with APP (amyloid precursor protein), tau (MAPT), and neuroinflammatory mediators (clusterin, TREM2) - critical for Alzheimer’s disease pathology
Complement and innate immunity: Interactions with complement factor H (CFH), TREM2, and alpha-2-macroglobulin (A2M) link APOE to neuroinflammation
Transcription factor regulatory data
APOE is not a transcription factor. It encodes apolipoprotein E, a structural lipoprotein involved in lipid transport, not a DNA-binding regulatory protein. Therefore, downstream target and DNA-binding motif sections are not applicable.
Upstream Regulators of APOE
APOE is regulated by 30 transcription factors identified in CollecTRI (curated transcription factor regulatory interactions):
High-Confidence Regulators:
- Activation: ATF4, NR1H3
- Repression: AP1, JUN
- Unknown/Unspecified: NFKB1, NFKB, IRF6, PPARD, TCF3, TFAP2A, TFAP2B, TP53, NR2C2, ZIC1, ZIC2, ZNF202
Low-Confidence Regulators:
- Activation: NR1H2, PPARG
- Repression/Unspecified: AEBP1, BHLHA15, CEBPG, FOXM1, NR1H4, RELA, SP1
No Confidence Rating:
- Activation: BMP2, DNAJA4, TREM2
- Repression: SPI1
- Unknown: STAT1
Evidence Type: All entries are from CollecTRI, a database combining ChIP-seq data, literature-curated interactions, and predicted binding. Confidence ratings range from High (experimental validation) to Low (predicted or limited evidence).
Drug & pharmacology data
APOE is NOT a primary drug target. While APOE (apolipoprotein E) is a critical genetic risk factor for Alzheimer’s disease and other conditions, it is not currently actively targeted by approved drugs or clinical-stage therapeutics.
Available data:
Drug associations: Only 8 compounds recorded in DrugBank interact with APOE:
- Minerals/supplements: Zinc (DB01593), zinc acetate (DB14487), zinc chloride (DB14533), zinc sulfate (DB14548), copper (DB09130)
- Pharmaceuticals: Sirolimus (DB00877), verteporfin (DB00460), infigratinib (DB11886)
These represent non-specific interactions or indirect effects rather than targeted APOE inhibition.
ChEMBL targeting data: Zero ChEMBL molecules are indexed as direct APOE-targeting agents.
Clinical trials: No ongoing clinical trials specifically targeting APOE therapeutically are documented in standard databases.
Pharmacogenomics: APOE variants (ε2/ε3/ε4 alleles) affect drug metabolism and response in multiple pathways, but PharmGKB contains minimal structured dosing guidance for APOE-based personalization.
Why APOE is not targeted: APOE is a structural protein involved in lipid transport. Unlike enzymes or receptors, APOE presents pharmacological challenges—inhibiting it directly would likely cause hepatic dysfunction. Instead, research focuses on modulating APOE-related pathways (e.g., lipid metabolism, neuroinflammation, amyloid clearance) rather than APOE itself.
Expression profiles
Tissue Expression (Bgee)
APOE shows ubiquitous expression across human tissues (expression breadth: ubiquitous; max score: 99.93; average: 88.4). Data compiled from 287 conditions with 261 gold-quality evidence entries.
| Rank | Tissue | Score | Quality |
|---|---|---|---|
| 1 | Right adrenal gland cortex | 99.93 | Gold |
| 2 | Left adrenal gland cortex | 99.93 | Gold |
| 3 | Left adrenal gland | 99.93 | Gold |
| 4 | Right adrenal gland | 99.92 | Gold |
| 5 | Right lobe of liver | 99.90 | Gold |
| 6 | Adrenal cortex | 99.90 | Gold |
| 7 | Nucleus accumbens | 99.82 | Gold |
| 8 | Adrenal gland | 99.80 | Gold |
| 9 | Amygdala | 99.76 | Gold |
| 10 | Liver | 99.65 | Gold |
| 11 | Hypothalamus | 99.57 | Gold |
| 12 | Caudate nucleus | 99.48 | Gold |
| 13 | C1 cervical spinal cord | 99.47 | Gold |
| 14 | Putamen | 99.45 | Gold |
| 15 | Right cerebellar hemisphere | 99.40 | Gold |
| 16 | Right frontal lobe | 99.38 | Gold |
| 17 | Spinal cord | 99.38 | Gold |
| 18 | Dorsal root ganglion | 99.27 | Gold |
| 19 | Lateral globus pallidus | 99.22 | Gold |
| 20 | Cerebellar cortex | 99.17 | Gold |
| 21 | Cerebellar hemisphere | 99.16 | Gold |
| 22 | Anterior cingulate cortex | 99.11 | Gold |
| 23 | Cingulate cortex | 99.07 | Gold |
| 24 | Right ovary | 99.05 | Gold |
| 25 | Adult mammalian kidney | 99.04 | Gold |
| 26 | Adrenal tissue | 99.02 | Gold |
| 27 | Skin of abdomen | 98.98 | Gold |
| 28 | Cerebellum | 98.90 | Gold |
| 29 | Right lung | 98.80 | Gold |
| 30 | Spleen | 98.76 | Gold |
Tissue-specific patterns: Strong enrichment in adrenal cortex (top 6 ranks), liver, and CNS tissues (nucleus accumbens, amygdala, brain regions, spinal cord). Consistent high expression across all major organs.
Single-Cell Expression (SCXA)
APOE is present in 50 SCXA experiments across 15,491 cell clusters with mean expression ranging 6.3–13,467 TPM (max: 13,467; average: 667).
Key datasets covering notable cell populations:
| Dataset | Description | Cells | Focus |
|---|---|---|---|
| E-ANND-5 | Developing human immune system (organs) | 911,873 | Immune cells, multi-tissue |
| E-HCAD-30 | T cells in human CNS | 109,642 | T cell subsets, CNS |
| E-HCAD-56 | Human spinal cord atlas | 245,394 | Spinal cord cell types |
| E-HCAD-9 | Human liver macrophages | 79,612 | Hepatic monocytes/macrophages |
| E-MTAB-6701 | Placental-maternal interface | 135,071 | Trophoblasts, immune, stromal |
| E-MTAB-8894 | Fetal lateral ganglionic eminence | 150,129 | Neural development |
| E-MTAB-10287 | Endometrial tissue | 340,047 | Epithelial, immune, stromal |
| E-HCAD-15 | Pulmonary fibrosis lung | 372,319 | Fibroblasts, myofibroblasts, epithelial |
| E-GEOD-134144 | Testis puberty development | 150,071 | Germ cells, Sertoli, Leydig |
| E-GEOD-137537 | Human retina | 12,881 | Photoreceptors, retinal neurons, glia |
Cell-type expression patterns: Highest expression detected in immune populations (macrophages, monocytes, dendritic cells), glial cells (astrocytes, microglia), and endothelial cells. Notable expression in hepatocytes and adipocytes.
Disease associations
Mendelian/Monogenic Diseases
| Disease | Disease ID | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Alzheimer disease 2 | OMIM:104310, MONDO:0007089, Orphanet:1020 | Autosomal dominant/Unknown | Definitive/Limited |
| Lipoprotein glomerulopathy | OMIM:611771, MONDO:0012725, Orphanet:329481 | Autosomal dominant | Strong/Moderate/Supportive |
| Hyperlipoproteinemia type 3 | OMIM:617347, MONDO:0018473 | Autosomal recessive/dominant | Strong/Moderate |
| Sea-blue histiocyte syndrome | OMIM:269600, MONDO:0010017 | Autosomal dominant | Limited/Supportive |
| Dysbetalipoproteinemia | Orphanet:412 | Unknown | Moderate |
Additional Mondo disease associations: Familial hypercholesterolemia (MONDO:0005439), Coumarin resistance (MONDO:0007390), Age-related macular degeneration 1 (MONDO:0011285), Alzheimer disease 3 & 4 (MONDO:0011913, MONDO:0011743), Coronary artery disease susceptibility (MONDO:0800425), Major depressive disorder (MONDO:0002009), Hyperlipoproteinemia (MONDO:0037748)
Phenotype Associations (HPO Terms)
Top 30 HPO terms linked to APOE (84 total):
- HP:0000726 – Dementia
- HP:0002511 – Alzheimer disease
- HP:0000083 – Renal insufficiency
- HP:0000093 – Proteinuria
- HP:0003124 – Hypercholesterolemia
- HP:0003141 – Increased LDL cholesterol concentration
- HP:0003233 – Decreased HDL cholesterol concentration
- HP:0002155 – Hypertriglyceridemia
- HP:0000608 – Macular degeneration
- HP:0001982 – Sea-blue histiocytosis
- HP:0002354 – Memory impairment
- HP:0100543 – Cognitive impairment
- HP:0001681 – Angina pectoris
- HP:0001013 – Eruptive xanthomas
- HP:0001084 – Corneal arcus
- HP:0001114 – Xanthelasma
- HP:0000819 – Diabetes mellitus
- HP:0004943 – Accelerated atherosclerosis
- HP:0005181 – Premature coronary artery atherosclerosis
- HP:0011970 – Cerebral amyloid angiopathy
- HP:0002185 – Neurofibrillary tangles
- HP:0100256 – Senile plaques
- HP:0001288 – Gait disturbance
- HP:0001300 – Parkinsonism
- HP:0000741 – Apathy
- HP:0000751 – Personality changes
- HP:0002071 – Abnormality of extrapyramidal motor function
- HP:0001397 – Hepatic steatosis
- HP:0001513 – Obesity
- HP:0000821 – Hypothyroidism
Complex Disease / GWAS Associations
Top 30 GWAS traits and diseases (200+ total studies):
| Trait/Disease | Study ID | Effect Size (P-value) | Mapped Gene(s) |
|---|---|---|---|
| Alzheimer’s disease (late onset) | GCST005549 | 3e-105 | APOE |
| LDL cholesterol levels | GCST006004 | 3.01e-322 | APOE |
| Total cholesterol levels | GCST004235 | 8e-315 | APOE |
| LDL cholesterol levels | GCST002222 | 2e-178 | APOC1 |
| Alzheimer’s disease | GCST000682 | 1e-295 | TOMM40 |
| Total cholesterol | GCST002221 | 1e-149 | APOC1 |
| Alzheimer’s disease | GCST001529 | 8e-149 | APOC1 |
| LDL cholesterol | GCST000759 | 9e-147 | APOC1 |
| HDL cholesterol | GCST006611 | 1e-142 | APOE |
| Total cholesterol | GCST006034 | 6e-187 | APOE |
| Cerebrospinal fluid AB1-42 levels | GCST004069 | 5e-94 | APOE |
| Cholesterol, total | GCST004209 | 5e-94 | APOE |
| Alzheimer’s disease | GCST001087 | 8e-89 | TOMM40 |
| Lipoprotein phospholipase A2 activity | GCST004963 | 8e-78 | APOE |
| Parental longevity (mother’s attained age) | GCST006696 | 1e-68 | APOE |
| Parental longevity (combined parental age) | GCST006697 | 1e-74 | APOE |
| Dementia with Lewy bodies | GCST005276 | 3e-64 | APOE |
| Cerebrospinal fluid t-tau:AB1-42 ratio | GCST006673 | 4e-26 | APOE |
| Coronary artery disease | GCST005196 | 3e-39 | APOE |
| Neuritic plaques or cerebral amyloid angiopathy | GCST005515 | 5e-40 | APOE |
| Lewy body disease | GCST002591 | 3e-11 to 5e-12 | APOE |
| Cognitive decline (age-related) | GCST002320 | 5e-19 | APOE |
| Cerebral amyloid deposition (PET imaging) | GCST003073 | 8e-32 | APOE |
| C-reactive protein levels | GCST006012 | 7e-36 | APOE |
| Age-related macular degeneration (advanced) | GCST003219 | 2e-42 | APOE |
| Response to statins (LDL change) | GCST001408 | 2e-47 | APOE |
| Type 2 diabetes | GCST003619 | 7e-09 | LNCOB1, NECTIN2 |
| Parental lifespan | GCST004983 | 1e-27 | APOE |
| Mortality | GCST005078 | 1e-20 | APOE |
| Metabolite levels | GCST001639 | 6e-42 | APOE - APOC1 |
Key GWAS findings: APOE is a major locus for lipid metabolism (cholesterol, LDL, HDL, triglycerides), Alzheimer’s disease and age-related cognitive decline, cardiovascular traits (coronary artery disease, atherosclerosis), age-related macular degeneration, lifespan and longevity, and CSF biomarkers (amyloid-beta, tau levels). Nearby genes APOC1 and TOMM40 show similar associations, indicating a highly pleiotropic region on chromosome 19.