Understanding Your APOE Status. Why Two SNPs Are Required
Your APOE genotype cannot be determined from a single genetic position. It requires reading two SNPs together: rs429358 (codon 112) and rs7412 (codon 158). The combination of your alleles at both positions determines which APOE isoforms you carry. Varia reads both positions from your raw file and resolves your complete APOE diplotype.
The APOE Isoform Table
| rs429358 | rs7412 | APOE Diplotype | Alzheimer's Risk | Notes |
|---|---|---|---|---|
| T,T | T,T | ε2/ε2 | Below average | Lowest AD risk; elevated Type III hyperlipoproteinemia risk |
| T,T | C,T | ε2/ε3 | Below average | Cardioprotective lipid profile |
| T,T | C,C | ε3/ε3 | Population average | Most common genotype globally |
| C,T | C,T | ε2/ε4 | Modestly elevated (~2-3x) | The ε4 allele drives the risk; the ε2 provides little offset |
| C,T | C,C | ε3/ε4 | ~3x elevated | ~25% of European-descent population |
| C,C | C,C | ε4/ε4 | ~12-15x elevated | ~2% (Northern European descent; lower in other populations) |
Risk figures are odds ratios for Alzheimer's diagnosis relative to the ε3/ε3 genotype, drawn from large APOE meta-analyses (APOE genotype and Alzheimer disease risk across age, sex, and population ancestry, JAMA Neurology 2023; foundational meta-analysis Farrer et al., JAMA 1997). They come largely from European-ancestry cohorts and vary by genetic ancestry: the association is strongest in East Asian populations and weaker in African-ancestry and Hispanic populations, so these multipliers do not transfer cleanly across ancestries. Frequencies are approximate and population-dependent.
Why 23andMe Cannot Report Your Full APOE Status
Since 2017 the FDA has limited 23andMe's APOE health reporting to rs429358, shown only under specific consent and educational modules; rs7412 is not in the health section. Without both SNPs the APOE diplotype cannot be resolved from 23andMe's health interface. Varia reads both positions directly from your raw data file, which does contain them, and resolves the complete diplotype. That restriction governs 23andMe's display, not your personal raw data.
Why AncestryDNA Results May Be Unreliable for APOE
AncestryDNA's chip array has a documented systematic reporting issue at rs429358. The ApoE4.Info community, one of the most active communities of APOE4-aware individuals, has reported for years that AncestryDNA raw data can list rs429358 as T/T even in individuals confirmed as ε3/ε4 or ε4/ε4 by 23andMe or clinical testing. In other words, some AncestryDNA users who appear ε3/ε3 from their raw data are actually ε3/ε4 or ε4/ε4. If you have only AncestryDNA data and your APOE result shows ε3/ε3, consider confirming with a 23andMe raw data file or a clinical APOE test when APOE status matters to you. Varia guards against this directly: when it detects an AncestryDNA file, it flags rs429358 as not reliably determinable rather than reporting a potentially false result.
How Varia Resolves Your APOE Diplotype
Varia reads both rs429358 and rs7412 from your raw file entirely within your browser. No upload, no server. For WGS VCF files from Sequencing.com or Dante Labs, both positions are present with high-confidence sequencing depth and are the most reliable source for APOE determination. For chip-based files, both positions are read and the AncestryDNA caveat is flagged explicitly in the Domain I results if an AncestryDNA file is detected.