SNPwatch: 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 that each copy of the G version of rs744373 near the BIN1 gene was associated with 1.13 times increased odds of Alzheimer’s compared to two copies of an A at this SNP.  They also found that each copy of the C version of rs597668 near the EXOC3L2/BLOC1S3/MARK4 genes was associated with 1.18 times increased odds of Alzheimer’s compared to two copies of a T.

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 rs597668, 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.

(See this Spittoon post for more information on the variants in CLU (clusterin) and PICALM. The current study failed to find support for an association between variations in a third gene mentioned in the previous Spittoon post, CR1, and Alzheimer’s.  23andMe customers can check their data for the newly identified variants rs744373 and rs597668 using the Browse Raw Data feature.)

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.

(For technical reasons, 23andMe cannot currently give customers information about their APOE status.  Our scientists are actively working on this problem.)

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.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.






  • Teri Thomas

    Great company, great ideas, and keep holding strong to provide tools directly to patients/the public. I’ve heard you’ve had some negative pressure and hope you can grow and thrive.

    I’ll be buying the complete edition eventually but the disease I’m most interested in is Alzheimers. When will that analysis be included in all other diseases profiled?

  • http://www.23andme.com ErinC

    @ Teri Thomas

    Thanks for the kind words!

    As explained in this post, there are technical reasons we are not currently able to offer information about the different versions of APOE (the gene with the strongest known effects on a person’s risk for Alzheimer’s). Our scientists are working on this problem and we will be sure to keep everyone posted on our progress.

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