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Researchers Spot A Region On Chromosome 10 That May Be Associated With The Majority of Cases of Alzheimer's
  
By Bijal P. Trivedi


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Two teams of researchers using entirely different approaches have homed in on the same region of chromosome 10 that they believe contains a new susceptibility gene for late-onset Alzheimer's disease. The two reports not only provide confirmation of the new gene's location but also give scientists an idea of the role it may play in causing a disease in which the genetic contributions have remained elusive. They were presented as late-breaking research news at the annual meeting of the American Society of Human Genetics in Philadelphia.


Dr. Alois Alzheimer (left) and some colleagues at a lake resort in southern Germany close to Munich, in around 1905. Using the microscope and new tissue-staining procedures, Dr. Alzheimer first characterized the brain abnormalities of the disease in 1906.

So far, four genes have been identified that cause early-onset Alzheimer's disease—a rare inherited form, which strikes between ages 30 and 55, but accounts for fewer than three percent of Alzheimer's cases. The remaining 97 percent of patients have the late-onset form of the disease that researchers believe is caused by an entirely different, and unknown, collection of genes. Alzheimer's affects more than 4 million people in the United States; about 10 percent of people over age 65 and more than half the adults over 85 are afflicted.

The brains of early-onset and late-onset Alzheimer's patients are almost indistinguishable, which suggests to many researchers that while the two forms may have different starting points, they might merge and follow a common route of progression. In both instances, the brain is speckled with spherical plaques made up of sticky and toxic amyloid beta proteins and the neurons are clogged with tangled masses of proteins that fill and eventually kill the cells. The result is a debilitating progressive neurological disorder that leads to the loss of memory, reasoning ability, and change in personality and behavior as the connections in the brain are disrupted by the accumulation of protein.


Left: The arrows show accumulations of the Tau protein inside individual neurons. Right: Two blood vessels are surrounded by collections of brown dots. These brown specks are sticky plaques of the Ab protein.

The first important clue about the genetic cause of late-onset Alzheimer's, and the observation that inspired the current research, came from Steven Younkin's laboratory at the Mayo Clinic in Jacksonville, Florida. Researchers noticed that all three genes that cause the rare early-onset form of the disease increase the level of amyloid beta 42 (Ab42), the plaque protein, in the blood plasma of young Alzheimer's patients. Relatives carrying a mutation in any of these genes also had high plasma levels of Ab42.

"Based on this we thought that maybe there were genes involved in late-onset Alzheimer's that acted in the same way and also raised Ab42 levels," says Younkin. The Florida team measured the plasma levels of Ab42 of late-onset patients, and their first-degree relatives and extended family members.

"We found that late-onset patients, and many of their relatives, who showed no behavioral signs of the disease, had Ab42 levels that were roughly twice as high as normal," says Nilufer Ertekin Taner, who led the project in Younkin's laboratory. The high levels of Ab42 among family members indicated that this trait had a genetic basis, and the team began a search for a gene that, if mutated, would increase Ab42.

Taner screened families of late-onset patients, chosen for their unusually high Ab42 levels, with genetic markers from several chromosomes. Using a computer program called SOLAR to analyze her data, Taner found that the markers on chromosome 10 gave a LOD score of 3.93—a number used by geneticists to indicate whether a particular region is associated with a disease or trait. The higher the LOD score, the closer a marker is to the gene responsible for the disease.

"A LOD score of three is usually considered evidence that the marker is linked to the disease, so a LOD score of 3.9 is pretty good," says Younkin.

While the Florida researchers were looking for genes affecting levels of Ab42, researchers led by Alison Goate at Washington University School of Medicine, in St. Louis, Missouri, approached the problem from another angle.


Top: A brain from a healthy person. Below: The brain of an Alzheimer's patient. In general, the brains show tremendous neuron death that causes the brain mass to shrink.

Instead of using large families as Taner did, Goate collected 429 pairs of siblings with Alzheimer's and screened them with genetic markers from all over the genome. The idea behind using pairs of siblings (sib-pairs) is that sibs share about 50 percent of their genetic material; if the sibs both share a trait or disease, they usually will have inherited it from the same parent. Goate looked for a genetic marker shared by the highest numbers of sib-pairs. About 64 percent of the sib-pairs shared a marker on chromosome 10; when the data was massaged the final LOD score was 3.83.

"What is really amazing is that two groups using completely different methods found linkage of late-onset Alzheimer's disease to exactly the same spot on chromosome 10. This confirmation of our work really elevates the results," says Younkin.

"Taner's study is actually more powerful because their results not only show linkage of that region of chromosome 10 to late onset, but their study design suggests that the gene is probably working by increasing levels of Ab42," says Goate.

The task now is to find the genes. The region of interest on chromosome 10 spans about 10 million base pairs and contains anywhere between 50 and 100 genes according to John Hardy, a collaborator of Goate at the Mayo Clinic, in Jacksonville.

Goate's team immediately examined the insulin-degrading enzyme, which is also known to degrade Ab proteins, that seemed like an obvious candidate for modifying Ab42 levels. A mutation in this gene could easily explain the large build-up of Ab42, which then forms the large toxic plaques. "But so far we haven't found any mutations in regions of the gene which make the enzyme," says Goate.

The bad news is that there are no other genes that jump out and look like convincing candidates for the role of Ab42 modifiers, says Hardy.

Hardy's concern, however, is that the mutation they seek will be tricky to detect. If the mutation is in the protein-coding region of the gene, then it will be "easy to sort out," says Hardy. But it is not easy if the genetic variation is in a regulatory region that controls the quantity of protein produced. "We can tell if a regulatory region can switch a gene off or on, but if a mutation changes the quantity of protein produced, well, we don't have sensitive enough assays to detect these subtle changes," says Hardy.

Both teams will try and narrow down the region before beginning their search for specific disease-causing mutations. Hardy proposes sequencing the entire region in late-onset patients, relatives with high Ab42, and unaffected individuals and searching for variations that could explain the disease. "It's a lot of work, and very tedious, but not impossible—it's what you have to do," says Hardy.

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