{"gene":{"symbol":"APOE","name":"Apolipoprotein E","protein":"Apolipoprotein E","ncbi_gene_id":"348","locus":"19q13.32","summary":"APOE encodes apolipoprotein E, a 299-amino-acid lipid-transport protein, and is the strongest common genetic risk factor for late-onset Alzheimer's disease and a major modulator of cardiovascular disease. The three classical alleles ε2, ε3 and ε4 are defined by combinations of two missense SNPs, rs429358 and rs7412. ε4 raises lifetime Alzheimer's risk and ε2 lowers it, with effect sizes among the largest in complex-disease genetics.","function":"Apolipoprotein E binds lipids to form lipoprotein particles. In plasma it is a major component of VLDL, IDL and a subset of HDL, is the ligand recognized by the LDL receptor and the LDL receptor-related protein, and drives clearance of triglyceride-rich lipoproteins. In the brain, where it is produced primarily by astrocytes, it shuttles cholesterol and phospholipids between cells and contributes to clearance of amyloid-β peptide. The three classical alleles differ at residue 112 (rs429358) and residue 158 (rs7412): ε3 (Cys112/Arg158) is the ancestral and most common allele; ε4 (Arg112/Arg158) binds lipid substrates differently and is less efficient at promoting amyloid-β clearance in experimental models; ε2 (Cys112/Cys158) binds the LDL receptor poorly, which can cause type III hyperlipoproteinemia in homozygotes but is also associated with lower lifetime Alzheimer's risk. Compared with ε3/ε3, the odds of Alzheimer's disease are about 3x higher in ε3/ε4 heterozygotes and about 15x higher in ε4/ε4 homozygotes in people of European ancestry, with earlier onset; ε2/ε3 carriers have about 40% lower odds.","category":"disease_risk","key_variants":[{"rsid":"rs429358","name":"Cys112Arg (exon 4, codon 112)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): T reference, C variant. The APOE isoform needs rs7412 as well: ε4 is C here with C at rs7412, ε3 is T with C, ε2 is T with T. Without phasing, two positions can't tell ε1/ε3 from ε2/ε4.","effect":"The C allele defines the ε4 allele, which is less efficient at promoting amyloid-β clearance in experimental models, raises Alzheimer's risk and is associated with slightly higher LDL cholesterol.","frequency_note":"ε4 frequency ~16% in Europeans, ~9% in East Asians, ~24% in Yoruba (1000 Genomes)."},{"rsid":"rs7412","name":"Arg158Cys (exon 4, codon 158)","alleles":"Plus strand, GRCh37 (as in 23andMe raw data): C reference, T variant. The APOE isoform needs rs429358 as well: ε2 is T here with T at rs429358, ε3 is C with T, ε4 is C with C.","effect":"The T allele defines the ε2 allele, which binds the LDL receptor poorly (type III hyperlipoproteinemia risk in homozygotes) and is associated with lower lifetime Alzheimer's risk.","frequency_note":"ε2 frequency ~6% in Europeans, ~10% in East Asians, ~11% in Yoruba (1000 Genomes)."}],"phenotypes":["ε3/ε3 (rs429358 T/T, rs7412 C/C): ~61% of Europeans; reference risk","ε3/ε4 (rs429358 T/C, rs7412 C/C): ~24% of Europeans; ~3x the odds of Alzheimer's disease (OR 3.2), slightly higher LDL cholesterol","ε4/ε4 (rs429358 C/C, rs7412 C/C): ~2% of Europeans; ~15x the odds of Alzheimer's disease (OR 14.9), earlier onset","ε2/ε3 (rs429358 T/T, rs7412 C/T): ~10% of Europeans; ~40% lower odds of Alzheimer's disease (OR 0.6)","ε2/ε4 (rs429358 T/C, rs7412 C/T): ~2% of Europeans; ~2.6x the odds of Alzheimer's disease (OR 2.6), between ε3/ε3 and ε3/ε4 (most often; without phasing, two positions cannot tell it from ε1/ε3)","ε2/ε2 (rs429358 T/T, rs7412 T/T): ~0.4% of Europeans; Alzheimer's odds estimate imprecise (OR 0.6, 95% CI 0.2–2.0); a minority develop type III hyperlipoproteinemia, usually with an additional metabolic factor"],"clinical_relevance":"ClinVar lists rs429358 (the ε4-defining variant) as a risk factor for Alzheimer's disease, among conflicting submissions; its single-variant record for rs7412 (ε2-defining) is classified as drug response (atorvastatin efficacy), and the ε2 link to familial dysbetalipoproteinemia (type III hyperlipoproteinemia) comes from the lipid literature. APOE is one of the few common variants where the effect on lifetime risk is large enough to be clinically meaningful in isolation, but several caveats matter as much as the genotype: ε4 is a risk factor, not a verdict (many ε4/ε4 homozygotes never develop dementia and many non-carriers do, and modifiable factors such as hypertension control, sleep, exercise, hearing protection, education and vascular risk management substantially alter absolute risk); there is currently no proven preventive treatment specific to ε4 carriers (lecanemab and donanemab are indicated at the mild cognitive impairment or mild dementia stage, are not preventive, and their FDA labels carry a boxed warning that ε4 homozygotes have a higher incidence of ARIA, with ApoE ε4 testing to be performed before treatment); pre-test counselling is recommended, since the result cannot be unlearned and may affect insurance access in some jurisdictions (in the EU, GDPR plus national rules; in the US, GINA covers health insurance and employment but not life, disability or long-term-care insurance); and only a minority of ε2/ε2 carriers develop type III hyperlipoproteinemia, typically with an additional metabolic factor (obesity, hypothyroidism, diabetes).","consumer_array_caveat":"Both rs429358 and rs7412 are usually present on consumer SNP arrays; 23andMe historically gated APOE behind an explicit opt-in because of the weight of the result. The two SNPs are translated into haplotypes as a pair (see phenotypes), and the ε2/ε4 combination cannot be told from ε1/ε3 without phasing. Before looking, consider whether the result is wanted, who else in the family it implicates (it is heritable), and whether genetic counselling is available; with a family history of early-onset dementia, a clinical geneticist, not a consumer report, is the right starting point.","drugs":[{"drug":"lecanemab","guideline":null,"level":null,"summary":"Amyloid-β-directed antibody indicated for Alzheimer's disease, started at the mild cognitive impairment or mild dementia stage; not a preventive drug. The FDA label carries a boxed warning for ARIA (amyloid-related imaging abnormalities): ApoE ε4 homozygotes have a higher incidence of ARIA, including symptomatic, serious and severe ARIA, than heterozygotes and noncarriers, and the label states ApoE ε4 testing should be performed before treatment starts."},{"drug":"donanemab","guideline":null,"level":null,"summary":"Amyloid-β-directed antibody indicated for Alzheimer's disease, started at the mild cognitive impairment or mild dementia stage; not a preventive drug. The FDA label carries a boxed warning for ARIA (amyloid-related imaging abnormalities): ApoE ε4 homozygotes have a higher incidence of ARIA, including symptomatic, serious and severe ARIA, than heterozygotes and noncarriers, and the label states ApoE ε4 testing should be performed before treatment starts."}],"sources":[{"label":"ClinVar — APOE entries","url":"https://www.ncbi.nlm.nih.gov/clinvar/?term=APOE%5Bgene%5D"},{"label":"OMIM 107741 — APOE","url":"https://www.omim.org/entry/107741"},{"label":"NCBI Gene 348","url":"https://www.ncbi.nlm.nih.gov/gene/348"},{"label":"Corder et al., Science 1993 (APOE ε4 gene dose, Alzheimer's risk and earlier onset in late-onset families)","url":"https://pubmed.ncbi.nlm.nih.gov/8346443/"},{"label":"Genin et al., Mol Psychiatry 2011 (APOE-dependent lifetime Alzheimer's risk)","url":"https://pubmed.ncbi.nlm.nih.gov/21556001/"},{"label":"Fortea et al., Nat Med 2024 (APOE4 homozygosity as a distinct genetic form of Alzheimer's disease)","url":"https://pubmed.ncbi.nlm.nih.gov/38710950/"},{"label":"Farrer et al., JAMA 1997 (APOE genotype and Alzheimer's disease odds ratios, meta-analysis)","url":"https://pubmed.ncbi.nlm.nih.gov/9343467/"},{"label":"ClinVar VCV000017864 — APOE c.388T>C (rs429358)","url":"https://www.ncbi.nlm.nih.gov/clinvar/variation/17864/"},{"label":"ClinVar VCV000017848 — APOE c.526C>T (rs7412)","url":"https://www.ncbi.nlm.nih.gov/clinvar/variation/17848/"},{"label":"FDA label, LEQEMBI (lecanemab) 2026 (indication; boxed warning on ARIA and ApoE ε4 testing)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d1ff786-e577-410a-a273-c4d7d0e4e975"},{"label":"FDA label, KISUNLA (donanemab) 2025 (indication; boxed warning on ARIA and ApoE ε4 testing)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=190352d4-ef62-4679-b4fa-e846e2766afa"},{"label":"Castellano et al., Sci Transl Med 2011 (apoE isoforms and brain amyloid-β clearance in mouse models)","url":"https://pubmed.ncbi.nlm.nih.gov/21715678/"},{"label":"Bennet et al., JAMA 2007 (APOE genotypes, LDL cholesterol and coronary risk, meta-analysis)","url":"https://pubmed.ncbi.nlm.nih.gov/17878422/"},{"label":"Khovidhunkit, Endotext 2025 (dysbetalipoproteinemia / type 3 hyperlipoproteinemia)","url":"https://pubmed.ncbi.nlm.nih.gov/39847660/"},{"label":"Ensembl GRCh37 rs429358 (1000 Genomes phase 3 population frequencies)","url":"https://grch37.ensembl.org/Homo_sapiens/Variation/Population?v=rs429358"},{"label":"Ensembl GRCh37 rs7412 (1000 Genomes phase 3 population frequencies)","url":"https://grch37.ensembl.org/Homo_sapiens/Variation/Population?v=rs7412"}],"related_blog":"/blog/genetic-risk-scores-explained/","disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information."},"meta":{"disclaimer":"Educational information only, not medical advice or diagnosis. Consult a clinician before acting on genetic information.","api_version":"2026-09-20","docs":"https://deepdna.ai/docs/","status":"live","data_as_of":"2026-10-25T21:32:19.251Z","freshness":"https://deepdna.ai/api/v1/freshness"}}