TORONTO - Two international research groups have identified a total of five new genes related to late-onset Alzheimer's disease and opened up new areas of research into what causes the progressive brain-destroying condition.
Details of the studies, one by the U.S.-led Alzheimer's Disease Genetics Consortium and the other by a European group headed by Cardiff University in Wales, are published in Sunday's issue of the journal Nature Genetics.
The consortium's identification of four new genes arose from the genetic analysis of a huge number of people from the United States, Canada and Europe -- about 54,000 in all. The European group pinpointed those four, plus a fifth gene, bringing the total number known to be implicated in the disease to nine.
"Each identified gene adds to the risk of dementia later in life," said Prof. Peter St George-Hyslop, whose team at the University of Toronto is part of the consortium, a collaborative effort involving investigators from 44 universities and research institutions. "This information provides great insight into the cause of Alzheimer's disease."
St George-Hyslop, director of the Tanz Centre for Research in Neurodegenerative Diseases, said many of the genes appear to be components of the same biochemical pathways in the brain.
"So we're now beginning to realize that these pathways are involved in causing the disease -- and we hadn't known that previously," he said.
The expanded genetic profile has given scientists new insights into the underlying mechanisms of the disease, including abnormal cholesterol metabolism and immune system-induced inflammation of brain cells.
"We knew a bit about the role of cholesterol and inflammation, but our assumptions up until very recently were that inflammation was sort of an end-stage thing that when you got nerve cells dying that there was inflammation involved in mopping up the dead cells," said St George-Hyslop.
"What these studies tell us actually is that that's absolutely wrong, that in fact inflammation is part and parcel of the disease, it's how it comes about. It's not an end-stage consequence. It's right there from the beginning."
Lead consortium researcher Gerard Schellenberg of the University of Pennsylvania said the identification of the genes is the culmination of years of work by the large number of scientists.
"Yet it is just the beginning in defining how genes influence memory and intellectual function as we age," Schellenberg said in a statement. "We are all tremendously excited by our progress so far, but much remains to be done, both in understanding the genetics and in defining how these genes influence the disease process."
Next on the research agenda will be learning how the genes activate inflammation and interfere with cholesterol metabolism, said St George-Hyslop.
"First of all, because these are early events in the disease, we may be able to measure inflammation in the brain or disordered cholesterol in the brain and use that as a test for someone who's in a very early stage of the disease, before they've actually got any symptoms.
"That's where you can intervene best in these sorts of diseases."
The new genetic information also points researchers in fresh directions when it comes to designing drugs that could stop the cascade of damaging biochemical reactions, potentially blocking the onset of the disease or at least slowing its progress.
Dr. Weihong Song, a Canada Research Chair in Alzheimer's Disease at the University of British Columbia, said zeroing in on the new genes adds credence to the notion that interaction between genetic makeup of individuals and other factors contributes to development of late-onset Alzheimer's.
"The study also provides new insight on identification of early diagnostic markers," Song, who was not involved in the research, said by email. As well, unique traits of the genetic information may be useful as a molecular diagnostic tool to predict people who are predisposed to dementia, he added.
"Obviously we still do not (know) how these genes contribute to the development of AD. Some in-depth research is needed to uncover the underlying mechanism. Furthermore, its significance in pharmocogenomics needs to be explored, i.e. could this group of genes be used to predict the patients' response to certain drugs or treatment?"
For St George-Hyslop, potential diagnostic information "is actually the least useful outcome of this (research) ... It probably will not be possible for someone to go and get a blood test and say,' Well, I've got gene X and therefore I'm going to get the disease.
"The real utility of this is that what it's done is it's opened up a new series of concepts to us that we previously hadn't been looking at," he said, adding that the findings have reinvigorated researchers trying to crack Alzheimer's code.
"What this suggests is that there are a couple of other targets that we can begin to chase down."
