Woman with Alzheimer's disease

Why ApoE4 increases Alzheimer's risk

10/4/07. By Oklahoma Medical Research Foundation

People with the ApoE4 gene are at higher risk for developing Alzheimer's disease. A new study helps explain why this is so.

Approximately 15 per cent of the population carries a gene that causes their bodies to produce a lipoprotein – a combination of fat and protein that transports lipids (fats) in the blood –known as apolipoprotein (Apo) E4. People who inherit the E4 gene from one parent are three times more likely than average to develop Alzheimer's; those who get the gene from both parents have a tenfold risk of developing the disease.

Research led by scientists at the Oklahoma Medical Research Foundation has now uncovered a molecular mechanism that links the susceptibility gene to the process of Alzheimer's disease onset. The findings appear in the 11 April issue of 'The Journal of Neuroscience'.

Jordan Tang and colleagues discovered that ApoE4 (along with other apolipoproteins) attaches itself to a particular receptor on the surface of brain cells. That receptor, in turn, adheres to a protein known as amyloid precursor protein. The brain cells then transport the entire protein mass inside.

Once inside, cutting enzymes – called proteases – attack the amyloid precursor protein. These cuts create protein fragments that, when present in the brain for long periods of time, are believed to cause the cell death, memory loss and neurological dysfunction characteristic of Alzheimer's.

Although researchers have known for more than a decade that ApoE4 was involved in development of Alzheimer's, Tang's study is the first to connect the process of protein fragment formation to ApoE4.

Approximately 1 in 7 people carry the E4 variant of ApoE; the remainder of the population carry variations known as E2 and E3. These individuals have a markedly lower incidence of Alzheimer's than those who carry the E4 gene. The new study found that ApoE4 produced more protein fragments than did E2 or E3.

"ApoE4 apparently interacts better with the receptor than its cousins," said Tang. "This may explain why people who carry the E4 gene have a higher risk of developing Alzheimer's."

"These findings may allow us to investigate the possibility of therapeutic intervention at different points in the process," said Tang. For example, he said, such efforts might focus on developing a compound to interfere with the receptor's ability to adhere to ApoE4.

Adapted from a news release by Oklahoma Medical Research Foundation.

Image: Elderly woman with Alzheimer's, courtesy of Libby Welch

Further reading

He X, et al. Apolipoprotein receptor 2 and X11{alpha}/{beta} mediate apolipoprotein E-induced endocytosis of amyloid-{beta} precursor protein and {beta}-secretase, leading to amyloid-{beta} production. J Neurosci. 2007 Apr 11;27(15):4052-4060. Abstract

Links

Jordan Tang research page

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