Vast Gene Study Yields Insights on Alzheimer’s
By GINA KOLATA
The two largest studies of Alzheimer’s disease have led to the discovery of no fewer than five genes that provide intriguing new clues to why the disease strikes and how it progresses.
Researchers say the studies, which analyzed the genes of more than 50,000 people in the United States and Europe, leave little doubt that the five genes make the disease more likely in the elderly and have something important to reveal about the disease’s process. They may also lead to ways to delay its onset or slow its progress.
“The level of evidence is very, very strong,” said Dr. Michael Boehnke, a professor of biostatistics at the University of Michigan and an outside adviser on the research. The two studies are being published Monday in the journal Nature Genetics.
For years, there have been unproven but persistent hints that cholesterol and inflammation are part of the disease process. People with high cholesterol are more likely to get the disease. Strokes and head injuries, which make Alzheimer’s more likely, also cause brain inflammation. Now, some of the newly discovered genes appear to bolster this line of thought, because some are involved with cholesterol and others are linked to inflammation or the transport of molecules inside cells.
The discoveries double the number of genes known to be involved in Alzheimer’s, to 10 from 5, giving scientists many new avenues to explore. One of the papers’ 155 authors, Dr. Richard Mayeux, chairman of neurology at Columbia University Medical Center, said the findings would “open up the field.”
And an expert who was not part of the studies, Dr. Nelson B. Freimer, who directs the Center for Neurobehavioral Genetics at the University of California, Los Angeles, said there were now enough unequivocal genes for Alzheimer’s disease that researchers could make real progress in figuring out its biology. “This is a big, solid step,” he said.
An estimated 5.4 million Americans have Alzheimer’s disease, most of whom are elderly. According to the Alzheimer’s Association, one in eight people over age 65 have the disease. Its annual cost to the nation is $183 billion.
By themselves, the genes are not nearly as important a factor as APOE, a gene discovered in 1995 that greatly increases risk for the disease: by 400 percent if a person inherits a copy from one parent, by 1,000 percent if from both parents.
In contrast, each of the new genes increases risk by no more than 10 to 15 percent; for that reason, they will not be used to decide if a person is likely to develop Alzheimer’s. APOE, which is involved in metabolizing cholesterol, “is in a class of its own,” said Dr. Rudolph Tanzi, a neurology professor at Harvard Medical School and an author of one of the papers.
But researchers say that even a slight increase in risk helps them in understanding the disease and developing new therapies. And like APOE, some of the newly discovered genes appear to be involved with cholesterol.
Of the 10 genes now known to be associated with Alzheimer’s in old age, four were found in the past few years and are confirmed by the new studies. APOE may have other roles in the disease, perhaps involved in clearing the brain of amyloids that pile up in plaques, the barnacle-like particles that dot the brain of Alzheimer’s patients and are the one unique pathological feature of the disease.
It is known that one of the first signs of Alzheimer’s disease is an accumulation of beta amyloid, or a-beta, a protein that forms plaques. And it is known that later in the disease, twisted and tangled proteins — tau — appear in dead and dying nerve cells.
But what is not known is why a-beta starts to accrue, why the brains of people with Alzheimer’s cannot get rid of its excess, or what is the link between amyloid and tau.
One of the new papers, by American investigators, analyzed the genes of 54,000 people, some with Alzheimer’s and others the same age but without the disease. They found four new genes.
The other paper is by researchers in Britain, France and other European countries with contributions from the United States. They confirmed the genes found by the American researchers and added one more gene.
The American study got started about three years ago when Gerard D. Schellenberg, a pathology professor at the University of Pennsylvania, went to the National Institutes of Health with a complaint and a proposal. Individual research groups had been doing their own genome studies but not having much success, because no one center had enough subjects.
In an interview, Dr. Schellenberg said that he had told Dr. Richard J. Hodes, director of the National Institute on Aging, the small genomic studies had to stop, and that Dr. Hodes had agreed.
These days, Dr. Hodes said, “the old model in which researchers jealously guarded their data is no longer applicable.”
So Dr. Schellenberg set out to gather all the data he could on Alzheimer’s patients and on healthy people of the same ages. The idea was to compare one million positions on each person’s genome to determine whether some genes were more common in those who had Alzheimer’s.
“I spent a lot of time being nice to people on the phone,” Dr. Schellenberg said.
He got what he wanted: nearly every Alzheimer’s center and Alzheimer’s geneticist in the country cooperated. Dr. Schellenberg and his colleagues used the mass of genetic data to do an analysis and find the genes and then, using two different populations, to confirm that the same genes were conferring the risk. That helped assure the investigators that they were not looking at a chance association.
It was a huge effort, Dr. Mayeux said. Many medical centers had Alzheimer’s patients’ tissue sitting in freezers. They had to extract the DNA and do genome scans.
“One of my jobs was to make sure the Alzheimer’s cases really were cases — that they had used some reasonable criteria” for diagnosis, Dr. Mayeux said. “And I had to be sure that people who were unaffected really were unaffected.”
Once the project got going, “we all realized we have to make this happen, it just had to happen,” he said. “Everyone wanted to collaborate.”
Meanwhile, the European group, led by Dr. Julie Williams of the School of Medicine at Cardiff University, was engaged in a similar effort. Dr. Schellenberg said the two groups compared their results and were reassured that they were largely finding the same genes. “If there were mistakes, we wouldn’t see the same things,” he added.
Now the European and American groups are pooling their data to do an enormous study, looking for genes in the combined samples.
“We are upping the sample size,” Dr. Schellenberg said. “We are pretty sure more stuff will pop out.”
