May 11, 2010 - Research

Large Study Identifies Two More Genetic Variants Associated with Alzheimer’s Disease

Understanding Alzheimer’s disease, the most common cause of dementia in people 65 years and older, is of the utmost importance as the population of the United States (and many other nations) becomes increasingly older.   Currently more than five million Americans are thought to have the disease, but by the year 2050 that number is estimated to reach 14 million unless a cure or prevention method is developed.

Until very recently, mutations in only one gene–APOE–had been conclusively associated with the more common late-onset form of Alzheimer’s (there are others associated with early-onset disease).   In September 2009 two groups studying large numbers of people identified variants in three new genes that had small effects on the disease.

Now researchers have pulled together the results of several studies and found variations in two more genes associated with increased risk.   The scientists, whose results appear online today in the Journal of the American Medical Association, suggest that these variants may be important for unraveling the underlying biology of Alzheimer’s, which will be essential in the quest to find new methods of treatment.

Researchers from the CHARGE, GERAD1 and EADI1 Alzheimer’s research consortia combined data from more than 35,000 people (more than 8,000 with Alzheimer’s) with European ancestry.   They found a variant near the BIN1 gene was associated with 1.13 times increased odds of Alzheimer’s.   They also found another variant near the EXOC3L2/BLOC1S3/MARK4 genes was associated with 1.18 times increased odds of Alzheimer’s.

The BIN1 gene encodes a protein that is highly expressed in the brain and known to be important in processes that are disrupted by the plaques that form in the brains of people with Alzheimer’s.   Two of the genes near , BLOC1S3 and MARK4, encode brain proteins that are also involved in processes that are known to be disrupted in Alzheimer’s disease.   The MARK4 protein in particular is interesting because it interacts with tau, the protein responsible for the tangles seen in the brains of people with Alzheimer’s .

Combined analysis of all of individuals studied also provided support for previously identified associations in the CLU and PICALM genes.

Compared to a model that uses only APOE status, age and sex, adding in a person’s information for the replicated SNPs in the CLU and PICALM genes did not substantially improve risk prediction.   The researchers note that in light of the small effect sizes of these SNPs, this is not unexpected.

“The value of these associations may lie in the insights they could provide for research into the pathophysiological mechanisms of AD [Alzheimer’s disease],” the authors write.

In an accompanying JAMA editorial, Nancy Pedersen of the Karolinska Institute in Stockholm, Sweden, points out that it’s not surprising that the new variants don’t add much to risk prediction, writing that this finding “only verifies the notion that AD is a polygenic disorder; i.e., that potentially tens of thousands of risk alleles, each with a small effect, are important for liability to disease.   What is remarkable is that the single gene APOE is as important as it is for this complex disorder.”

Pedersen’s opinion is that researchers should forgo further pursuit of new genetic variants or replications of already identified SNPs, and instead turn their attention to the study of environmental risk and protective factors for Alzheimer’s disease.   She notes that in identical twins, there is at most a 61% chance that both twins will end up with the disease, indicating that non-genetic factors play an important role.   Further, she points outs that Alzheimer’s disease that sets in very late in life has been shown to be less heritable, suggesting that environment gets more and more important as people age.

Pedersen ends by noting that right now, the most important thing doctors can do is encourage people to make lifestyle changes, especially those that improve cardiovascular health, that may reduce the risk of dementia or at least postpone it.

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