ApoE

rs429358 + rs7412

APOE encodes a transport protein for cholesterol and other lipids. Two SNPs define the three isoforms ε2, ε3 and ε4. The ε4 form raises the risk of Alzheimer's and cardiovascular disease, the ε2 form lowers the Alzheimer risk. It is a risk marker, not a fate.

ApoE · ISOFORM FROM TWO SNPs ApoE ε2 rs429358T · Cys112 rs7412T · Cys158 Alzheimer risk ↓ rare, possible lipid hint ApoE ε3 rs429358T · Cys112 rs7412C · Arg158 reference most common variant ApoE ε4 rs429358C · Arg112 rs7412C · Arg158 Alzheimer risk ↑ dose-dependent, not a fate Everyone carries two ε alleles (e.g. ε3/ε4). The combination counts, not a single SNP.

The three isoforms from two SNPs

The isoform is set by two amino acid positions: 112 (rs429358) and 158 (rs7412). ε3, the most common form, carries cysteine at 112 and arginine at 158. ε4 arises when rs429358 carries the C allele (arginine at 112). ε2 arises when rs7412 carries the T allele (cysteine at 158). Only both SNPs together yield the ε combination.

What the risk means

In cohorts of European ancestry one ε4 allele goes along with roughly a three- to fourfold, two ε4 alleles with about a ten- to fifteenfold Alzheimer risk, each relative to ε3/ε3. That is an elevated risk, not a diagnosis: age, lifestyle, sex and other genes shift the picture strongly. ε4 also tends to raise LDL cholesterol.

Caution in interpretation

Knowing ε4 status can burden a person without offering an action, as long as no effective prevention is established. Genome only presents the technical genotype. Anyone learning their status should do so in context and ideally with counselling.

What Genome measures. The genotypes at rs429358 and rs7412, from which the ε isoform combination is derived (for example ε3/ε4).

Related topics

rsIDs, microarray and SNP lookupDisease associationsPolygenic scores

Sources

  1. 1Corder et al., 1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921–923. doi.org/10.1126/science.8346443
  2. 2Liu et al., 2013 Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology 9:106–118. doi.org/10.1038/nrneurol.2012.263