The APOE gene can increase the risk for heart disease. The heart risk is related to blood cholesterol and other fats. The APOE gene can increase the risk for Alzheimer’s dementia. The dementia risk is related to – well, it’s not well worked out. Several possibilities are proposed.
APOE is sometimes written ApoE, but the National Institutes of Health (USA) says the preferred or “official” way is APOE. The APOE gene controls the production apolipoprotein E. APOE is also used to refer to the apolipoprotein
What are Apolipoproteins?
Apolipoproteins are proteins that are acknowledged as movers of blood fats. “Apo” comes from Greek and means away or asunder. There are six major human apolipoproteins, A, B, C, D, E, and H. Heart disease and Alzheimer's dementia have been linked to apolipoprotein E.
The first discovered role of apolipoproteins was to encapsulate blood fat and carry it to specific cells. Blood fats (lipids) are not dissolved. They are submicroscopic globules. Apolipoproteins can attach to lipids. Fat-laden apolipoprotein E complexes carry lipids to the liver and dock in liver LDL receptors. Then, by a process of endocytosis, the apolipoprotein-fat complexes enter the liver cells, where they become uncoupled, freeing the fat for the liver cells’ discretional use.
The Bad APOE
APOE (the apolipoprotein) is essential to maintain cholesterol balance in the body. It’s made in the liver. A surprise to many, it’s also made in the brain, by glial cells. It’s made of 299 amino acids and maps to chromosome 19. The APOE gene is polymorphic – the gene has different possibilities. APOE has three possibilities, ε2, ε3, and ε4.
APOE ε4 is the villain in this story. Humans have matched sets of genes, one from the mother and one from the father. (Here we are talking about nuclear genes; mitochondrial genes are uniquely from the mother.) About 20% of humans have one ε4; about 2% have double ε4. A single ε4 increases the risk of heart disease. Double ε4 greatly increases the risk of heart disease. One explanation is that apolipoprotein ε4 is not effective in scooping up cholesterol and depositing it in liver cells. This lets cholesterol accumulate in the blood where it will clog up arteries in atherosclerotic plaques.
APOE and Alzheimer’s
The risk from APOE ε4 for heart disease is mirrored in the risk for Alzheimer's ("Alzheimer Disease Overview", by Thomas D. Bird, MD, on the website Gene Reviews, last revised July 24, 2008). The risk for those with one ε4 is three times, and double ε4 is 10 to 30 times higher than usual.
While heart disease risk is felt to be from poor clearance of blood fat by APOE ε4, that may not be the mechanism for the Alzheimer's risk.
It turns out that APOEs dissolve amyloid. Amyloid is believed to be the substance which, in higher levels, destroys brain cells and leads to Alzheimer's. APOE ε4 does a poor job of dissolving amyloid, and allows it (or its toxic precursors) to build up.
Possible Further Role of APOE
APOE docks on LDL receptors. LDL receptors on liver cells accept the fat, and that seems to be their function. But LDL receptors, or similar receptors, are on most other cells, including brain cells, where they have no apparent role in fat transport. Instead, they have a signaling function – they give instructions for the cell to modify its action. This signaling role could be the key to how APOE affects risk of Alzheimer's, and could lead to exciting new treatment possibilities. Suppose, for example, brain cell LDL receptors could be made to reduce production of amyloid: that could possibly prevent Alzheimer's.
Risk Does Not Mean Disease
Everyone with APOE ε4 does not get Alzheimer's. Everyone with Alzheimer's does not have APOE ε4. Alzheimer’s risk is multifactorial – it takes a combination of genetic and environmental factors to produce the disease. APOE genes are probably not the only genes involved in sporadic Alzheimer's dementia.
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