APOE genotype (genetics)

The APOE genotype (ε2/ε3/ε4) influences cholesterol transport and the inflammatory response. The APOE4 variant is associated on average with higher LDL cholesterol; studies have also observed a stronger inflammatory response. APOE2 is associated on average with lower LDL cholesterol; if both copies of the gene carry ε2, however, the breakdown of certain fat transporters can slow down. A single blood draw at the practice.

What the APOE gene does in the body

The APOE gene contains the blueprint for apolipoprotein E, a protein made mainly in the liver and, in the brain, by astrocytes. Apolipoprotein E sits on the surface of fat-transporting particles – the remnants of chylomicrons from dietary fat absorption, VLDL, IDL and part of HDL – and acts as a recognition signal: the liver takes up these particles via the LDL receptor and the related receptor LRP1. In the brain it carries cholesterol and other fats from astrocytes to nerve cells, which use them to build membranes and synapses. Everyone inherits two copies of the gene, one from each parent; the genotype stays the same throughout life.

What distinguishes the APOE variants ε2, ε3 and ε4?

The three variants differ at only two points in the protein chain, positions 112 and 158: ε2 carries the amino acid cysteine at both, ε3 carries cysteine and arginine, and ε4 carries arginine at both. These small differences change the shape of the protein – and with it how tightly it binds to the LDL receptor and which fat transporters it prefers. ε3 is the most common variant worldwide and serves as the reference. The three variants give rise to six possible genotypes, from ε2/ε2 to ε4/ε4.

What does the APOE ε4 variant mean for fat metabolism?

Apolipoprotein E4 preferentially attaches to the large, triglyceride-rich particles such as VLDL. As a result the liver takes up their remnants quickly, and its cholesterol content rises. The liver cell responds by making fewer LDL receptors – LDL cholesterol is then cleared from the blood more slowly, and the LDL level is higher on average. In the brain apolipoprotein E4 is less stable, transports fats less well and, in studies, helps less with removing the protein amyloid-β. In large studies ε4 was associated with a higher risk of arteriosclerosis and of Alzheimer's disease; many carriers do not develop these conditions, however, because numerous other factors play a part.

What does the APOE ε2 variant mean for fat metabolism?

Apolipoprotein E2 binds only weakly to the LDL receptor. The remnants of chylomicrons and VLDL are therefore taken up more slowly by the liver; the liver cell receives less cholesterol, makes more LDL receptors, and the LDL level is lower on average. In studies ε2 was associated with a lower risk of Alzheimer's disease. If both copies of the gene carry ε2, however, the fat remnants can build up in the blood: when a further factor is added, such as excess weight, diabetes or an underactive thyroid, a lipid disorder with raised cholesterol and triglyceride levels can develop, known as dysbetalipoproteinaemia.

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