Researchers discover gene contributing to Alzheimer's
CAROLYN ABRAHAM
From Monday's Globe and Mail
Scientists have taken a major step closer to understanding one of the causes of Alzheimer's disease and identifying people who run a higher risk of losing their minds and lives to the condition in their later years.
An international research effort has discovered a gene that, when defective, results in the buildup of a toxic protein byproduct in the brain and contributes to the onset of Alzheimer's around age 70.
Scientists estimate that people who carry mutated versions of the gene, known as SORL1, could face as much as a twofold increase in the risk of developing Alzheimer's, compared to the average.
The findings, based on DNA samples from 6,000 people, were replicated in four ethnic groups and confirmed in nine separate DNA collections, which included about 200 families from Canada, sporadic cases, healthy control subjects and the corpses of Alzheimer's patients.
"This gene is robustly associated with an increased risk of the most common form of Alzheimer's in several different ethnic groups," said Peter St. George-Hyslop, director of the Centre for Research in Neurodegenerative Diseases at the University of Toronto.
Toronto researchers, together with colleagues at Columbia University, Boston University and the Mayo Clinic, believe their five-year effort could lead to better ways to diagnose, treat or, perhaps, even prevent Alzheimer's in much the same way drugs are used to stave off heart disease.
Dr. St. George-Hyslop cautioned, however, that it is premature for anyone in the general population to gain anything meaningful from being screened.
Currently, there is no medication that halts the progression of Alzheimer's, nor is there a cure. Yet it is one of the fastest-growing fatal conditions as the population ages, striking one in 10 people older than 65.
"Cardiovascular disease, we are treating in a preventive mode, hopefully we can develop a similar approach to Alzheimer's disease," said study researcher Steve Younkin, head of pharmacology at the Mayo Clinic College in Florida.
The new discovery, to be published in the journal Nature Genetics, marks the second major gene linked to late onset Alzheimer's, the most common form of the disease.
The first, a gene mutation called apoliprotein E-4, or ApoE-4, was pinpointed in 1993 and is estimated to increase a carrier's risk of Alzheimer's around age 60 by 2½ times the average, Dr. St. George-Hyslop said.
Although the new gene does not appear to have as powerful an impact on susceptibility, Dr. St. George-Hyslop said the study suggests that variants within the gene could be more common risk factors than ApoE-4.
Researchers have not pinpointed the exact mutations in the SORL1 gene that cause disease, and evidence suggests the gene could have two or more defects. But they did find that changes in this gene were associated with Alzheimer's in people of Northern European, Caribbean-Hispanic, African-American and Arab-Israeli descent.
Interestingly, they also found that Arab-Israeli and Caribbean-Hispanic populations show exactly the same changes in the gene, suggesting the two groups once shared a common genetic or geographic heritage. "It's highly unlikely that this is due to chance," said co-author Lindsay Farrer, chief of the genetics program at the Boston University School of Medicine.
In rare cases, Alzheimer's can strike people in their 30s and 40s because of two known defective genes that make it a 99-per-cent certainty the disease will develop.
But 90 per cent of the time, Alzheimer's hits elderly people and is believed to be the result of a complex interplay of genetic and environmental factors.
Roughly a dozen genes have been linked to the condition. But many of those associations have remained loose and questionable because some people with the disorder do not carry these gene types and some who do never go on to develop Alzheimer's.
The field has not been "easy to disentangle," Dr. Farrer said.
"Maybe some reason people with the elevated risk gene don't get [Alzheimer's] is that there may be other protective genes at work or things in the environment that protect them."
In their study, researchers found that changes in the gene were more common in people with Alzheimer's than in healthy people of the same age.
Although they still have to identify the disease-causing mutations and test their prevalence in the general population, the researchers said they feel the finding will hold up.
"One of the reasons we're very encouraged by our findings," Dr. Farrer said, "is that we've observed this association [between the SORL1 gene and the disease] in many different data sets -- nine. We have internal replication built in many-fold."
The work began in the mid-1990s when Richard Mayeux, co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University in New York, began studying elderly residents of Washington Heights, a largely Hispanic neighbourhood in Northern Manhattan.
He found that people from the Dominican Republic have about three times the rate of Alzheimer's compared with people of other ethnic backgrounds.
Dr. Mayeux, working with long-time collaborator Dr. St. George-Hyslop, began to search for the genetic factors that might explain this. Initially, they discovered the Hispanic population carried a high rate of the defective genes linked to early onset Alzheimer's.
But from there, Dr. St. George-Hyslop explained, they decided to look for genes that might be involved in "trafficking" the so-called amyloid precursor protein, or APP, through a cell.
An overload of a toxic byproduct derived from APP is known to be the trigger that causes Alzheimer's. That APP byproduct wreaks havoc first on brain cells involved in memory and learning. But damage eventually spreads to other brain regions, leading to the failure of essential body systems.
Dr. St. George-Hyslop, one of the world's leading Alzheimer's researchers, explained that the APP is made "deep in the cell" and is then sent to the surface where its function is unclear. It's then reabsorbed into the cell where it can either be recycled and sent out to the surface again, or "float off into the forbidden zone" where its toxic byproduct is made.
The SORL1 gene produces a molecule that binds to the protein and forces it away from this dangerous fate. When it is defective, the amount of the toxic form of the protein builds up.
People can inherit defective copies of the SORL1 gene. But Dr. St. George-Hyslop said this "lifelong" defect does not result in disease until later in life because the effect is cumulative.
"We don't believe this is a disorder that develops six months before the disease [becomes apparent]," Dr. St. George-Hyslop said. "You can see changes going on in the brains of these patients 10 to 15 years before disease develops.
"At the moment, it's not very useful to tell people about these fuzzy risk factors," he said, "until we have a treatment for it."
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