Microarray & SNPs

ApoE

rs429358 + rs7412

APOE encodes a transport protein for cholesterol and other lipids. Two SNPs define the common ε2, ε3 and ε4 isoforms. ε4 is associated with higher Alzheimer's risk, while ε2 is generally associated with lower risk. The strength and meaning of these associations depend in part on age, sex and ancestry. Genotype alone does not predict whether or when someone will develop the disease.

Key points

  • ε4 is associated with higher average risk; two copies further change the risk context.
  • ε2 is protective for Alzheimer's but is associated with type III hyperlipoproteinemia.
  • Penetrance is incomplete: many ε4 carriers never develop disease, many patients carry no ε4.
ApoE · ISOFORM FROM TWO SNPsApoE ε2rs429358T · Cys112rs7412T · Cys158Alzheimer risk ↓rare, possible lipid hintApoE ε3rs429358T · Cys112rs7412C · Arg158referencemost common variantApoE ε4rs429358C · Arg112rs7412C · Arg158Alzheimer risk ↑dose-dependent, not a fateEveryone 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

ε4 is associated with higher average Alzheimer's risk in many populations, but the strength of the association differs by ancestry, age and sex. Relative group estimates cannot be converted directly into an individual's probability or age of onset. Individual assessment would require additional factors and would still be uncertain.

Caution in interpretation

An APOE result can raise personal questions. Genotype alone does not determine screening, treatment or another action. Genome displays the technical variant and does not replace confirmation by an appropriate clinical method or genetic 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