January 14, 2007
SORL1 Genetic Risks For Alzheimer's Disease

Want to know if you'll slowly lose all your memory and control of your body in your 70s and 80s? Probably not. Hopefully a cure for Alzheimer's won't take more than 10 or 15 years and any genetic risk you have for Alzheimer's will never get a chance to slowly destroy your mind. . But if you want to know if you are at risk a research team has identified yet another genetic variation that increases the risk of late-onset Alzheimer's Disease.

Researchers led by Howard Hughes Medical Institute (HHMI) international research scholar Peter St George-Hyslop have identified a new genetic risk factor associated with the most common form of Alzheimer's disease. The research implicates a gene called SORL1 in late-onset Alzheimer's, which usually strikes after age 65.

In an advance online publication in Nature Genetics on January 14, 2007, St George-Hyslop and colleagues connected the gene to the disease in six different groups of people, although they did not pinpoint the exact genetic mutations in SORL1 responsible for Alzheimer's. In their studies, the researchers used databases that include genetic information about people with and without Alzheimer’s disease. More than 6,800 individuals—45.8 percent of them affected with the disease—were included in the analysis, which is considered a large data set in the field, said St George-Hyslop..

These SORL1 variations join apolipoprotein E variation ApoE4 as known genetic risks for late onset Alzheimer's.

“We looked for variations of SORL1 in nine different groups of people and found those variations to be associated with an increased risk of Alzheimer's in six of them,” St George-Hyslop said. “That implies that SORL1 is not the only cause of Alzheimer's, but it's one of several. Some people with the disease will have a SORL1-related cause, and some won't.” St George-Hyslop is a professor in the department of medicine and director of the Center for Research in Neurodegenerative Disease at the University of Toronto and an HHMI international research scholar. Through its international research scholars program, HHMI supports leading scientists in 28 countries outside the United States.

The researchers studied several groups of Caucasians, one group of African Americans, one group of Hispanics from the Dominican Republic, and a group of Israeli Arabs. They tracked the SORL1 genes via single nucleotide polymorphisms, or SNPs, which are single-letter changes in a gene's sequence. They found that the Caucasians with Alzheimer's displayed a certain SNP signature at one end of the gene, while the African Americans, Hispanics, and Israeli Arabs with the disease displayed another SNP signature. “This implies that there are at least two, and possibly more, gene variants at work here,” said St George-Hyslop. “That's not unusual—in many diseases you see multiple variations that all impact a specific gene.”

So how can the scientists know that a gene has a genetic variation that contributes to a disease without knowing which particular genetic variation is responsible? See the mention of SNPs (single nucleotide polymorphisms) above. Those are locations in the genome where groups of people have single letter differences in their DNA as compared to all other groups of people. SNPs tend to occur in groups. Suppose at a particular location you have a letter A in your genome. Suppose other people have a G in that location and those who have a G have greater risk of Alzheimer's. That G usually will occur along with a group of other SNPs in nearby locations. The A at the same location will occur with letters at the same nearby SNP locations. The puzzle is to figure out which of other other nearby SNPs is the one that contributes to a disease risk.

The cost of testing for SNPs in genes is declining because chips are coming to market that can test for the presence of hundreds of thousands of SNPs at a time. The decline in SNP testing costs is enabling a growing flood of successful searches for genetic variations that contribute to disease risks. Within 5 years time I expect the number of discovered and easily testable genetic risk factors will become large enough to make personal DNA testing worthwhile.

But which risks will be worth testing for? Those you'll be able to do something about. Suppose a genetic variation makes Alzheimer's inevitable at middle age and that diet has little influence on when you'll get it. Well, I guess you could decide to avoid taking on family responsibilities that you won't be around to fulfill. But initially the biggest potential for doing something about a risk will involve risks that can be influenced by diet or exercise. What we need: genetic sample collection on big population studies of diets and lifestyles. Existing on-going longitudinal studies of diet and lifestyle risks could have their diet and lifestyle information compared against disease outcomes for those with high genetic disease risk to see if any dietary factors delayed or reduced the risk of major diseases.

What you should do when you discover 5 or 10 years hence that you have high genetic risk of a disease: Write your elected officials and argue for more research on the disease you are on course to get. Lobby for cures for diseases that will otherwise kill you and your loved ones.

Update: If the result with SORL1 is replicated it will join 14 other genes which have variations which are known risk factors for Alzheimer's.

Two geneticists at Massachusetts General Hospital, Lars Bertram and Rudolph Tanzi, have tried to bring order to this confused field by combining the data from many different studies. In an article in Nature Genetics earlier this month, they presented a group of 13 genes besides apolipoprotein E that have a statistically significant association with Alzheimer’s.

Dr. Tanzi said that he had run the numbers on SORL1 and that it would qualify at present for a place in his canon. “This is another gene worth paying attention to,” he added, “but we really have to wait for more replications.”

Over on the Gene Expression blog Amnestic points to evidence that APOE4 boosts episodic memory when young at the expense of greater Alzheimer's risk when you get old. APOE4 might be a variation worth having for someone being born now. The short term advantage might not cost you anything in the long run becaus 50 years from now Alzheimer's will be easily preventable.

We are going to find that many genetic variations which increase disease risks also provide benefits. The task of choosing ideal genetic variations for offspring will not be straightforward with a simple list of good genes and another list of bad genes. The best trade-offs will depend on guesses about the future availability of technologies, guesses about the shape of future societies, and one's values.

Share |      Randall Parker, 2007 January 14 03:26 PM  Brain Alzheimers Disease

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