rs429358 — APOE E4 determinant

Lipid metabolism and Alzheimer's risk - E4 carriers respond worse to high saturated fat

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APOE — The Cholesterol & Brain Health Gene

APOE11 Apolipoprotein E is a protein that helps transport cholesterol and other fats through the bloodstream is one of the most important genes in human genetics. It affects cholesterol transport, brain health, and longevity. Your APOE genotype is determined by two variants: rs429358 (this one, the E4 determinant) and rs7412 (the E2 determinant).

The Mechanism

The rs429358 variant causes a missense change at position 130 of the APOE protein, substituting cysteine with arginine (p.Cys130Arg). This single amino acid change defines the APOE ε4 isoform, which has reduced ability to clear LDL cholesterol from the bloodstream and impaired amyloid-beta clearance in the brain.

APOE Genotypes

The combination of rs429358 and rs7412 gives you one of six APOE genotypes: ε2/ε2, ε2/ε3, ε3/ε3, ε3/ε4, ε2/ε4, or ε4/ε4. ε3/ε3 is the most common (about 60% of people). The ε4 allele frequency varies dramatically across populations — from ~7% in South Asians to ~27% in sub-Saharan Africans.

The Evidence

The landmark study by Corder et al.22 landmark study by Corder et al.
Corder et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 1993 showed that each ε4 allele increases Alzheimer's risk and lowers age at onset. Risk increased from 20% to 90% with increasing ε4 dose.

A major meta-analysis33 major meta-analysis
Farrer et al. Effects of age, sex, and ethnicity on the association between APOE genotype and Alzheimer disease. JAMA, 1997 of 5,930 AD patients and 8,607 controls confirmed that one ε4 copy roughly triples risk (OR ~3.2 for ε3/ε4) and two copies raise it about 15-fold (OR ~14.9 for ε4/ε4). The effect is strongest in Caucasians and Japanese, weaker in African Americans and Hispanics.

E4 and Saturated Fat

APOE E4 carriers have a stronger negative response to dietary saturated fat. Their LDL cholesterol rises more sharply with saturated fat intake compared to non-carriers. This makes dietary fat choices particularly important for E4 carriers.

E4 and Alzheimer's

Each E4 allele increases Alzheimer's risk44 One E4 copy roughly triples risk; two copies raise it roughly 12-15-fold, though absolute risk still depends on many other factors including age, sex, and lifestyle, but it's not deterministic. Lifestyle factors — exercise, diet, sleep, cognitive engagement — can significantly modify this risk.

Interactions

APOE E4 risk compounds with TCF7L2 (rs7903146) — if you carry risk alleles at both, limiting dietary fat is especially important. The rs429358 and rs7412 variants together determine your complete APOE genotype.

Nutrient Interactions

saturated fat altered_metabolism
omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT No E4 Normal

No APOE E4 - normal fat tolerance

You do not carry the APOE E4 allele. About 72% of people share this genotype. Your lipid levels respond normally to dietary fat, giving you more dietary flexibility.

CT E4 Carrier Intermediate

One APOE E4 - limit saturated fat

You carry one APOE E4 allele, a genotype found in about 25% of the population. E4 carriers have a stronger negative response to high saturated fat intake — LDL cholesterol rises more than in non-carriers.

E4 is also associated with roughly 3-fold increased Alzheimer's risk, though lifestyle factors can significantly modify this. The effect varies by ancestry — weaker in African Americans, stronger in Japanese and Caucasian populations.

CC E4/E4 Homozygous High Risk

APOE E4/E4 - strict saturated fat limit

You carry two APOE E4 alleles, a genotype found in about 2-3% of the population. You have the strongest genetic response to dietary saturated fat — your LDL cholesterol rises substantially with high saturated fat intake.

This genotype is also associated with approximately 12-15-fold increased Alzheimer's risk compared to E3/E3, but lifestyle interventions (exercise, diet, sleep) can meaningfully modify this risk.