The "Alzheimer's Gene"
This web page was produced as an assignment for an undergraduate course at Davidson College.
Scientific Article: "Susceptibility Locus for Alzheimer's Disease on Chromosome 10"
This article, published in Science, on December 22nd, 2000, reported a two-stage genome-wide investigation on the susceptibility loci for sibling pairs with late onset Alzheimer's disease (LOAD) performed in the University of Wales. They reported that until then, the apolipoprotein E (APOE) gene had been the only identified genetic risk factor linked to LOAD, specifically the E4 allele of this gene. However, 50% of LOAD cases do not have the APOE4 allele, indicating that there must be other important risk factors involved in the susceptibility to LOAD.
Fig. 1: Chime image of the apolipoprotein suspect in LOAD.
To perform their study, the researchers screened DNA from affected Caucasian sibling pairs (termed ASPs). In stage 1, 292 ASPs were genotyped and data were analyzed using non parametric methods. 16 chromosomal regions were found showing an lod* score (multipoint linkage analysis) greater than one, and of those 16, 4 met the criteria for "suggestive linkage" laid out by E. Lander and L. Kruglyak (Nature Genet. 8, 237, 1999).
* Note: An lod score is a calculation of estimated linkage distance. It is derived from the following equation:
taken from Philip McLean, 1998.
In stage 2, 168 additional samples were obtained (from other areas of the UK and from the US) and 15 additional markers in a narrower area of chromosome 10 were genotyped in a total of 429 ASPs. It was discovered that the sibling pairs generally share 50% of alleles at the average locus. Surprisingly, for the marker D10S1211, allele sharing was elevated to 64%. This was true for both samples where ASPs had at least one APOE4 allele (APOE4+ve), and for those that had none (APOE4-ve). Multipoint linkage analyses were carried out and divided into three groups: whole sample, APOE4+ve, and APOE4-ve. Through the data (pictured below), the authors concluded that APOE4 status did not change the proportion of allelic sharing at this marker.
Figure 2. Original data graph taken from Science, including the reference to Ertekin-Tanner, et al.
Through their investigation, the authors confirmed that this area on chromosome 10 shows strong evidence for being a susceptibility locus for LOAD. The lod scores found for these markers are also reportedly higher than that found for the APOE4 allele on chromosome 19, making this possibly a larger risk factor for LOAD than APOE4.
It is important to note that a collaboration existed between this group and Ertekin-Tanner et al. who published their findings in the same journal. Ertekin-Tanner et al. found evidence of a "quantitative trait locus for high Aβ42 levels" that has been found to map to the same region on chromosome 10. These two studies together could imply that the possible LOAD allele identified increases chances for Alzheimer's Disease by modifying metabolism of that protein.
Popular Press: "Alzheimer's Gene Discovery"
An article published by BBC News online on December 23rd of 2000, reported on the findings of Michael Owen and Dr. Julie Williams, of the University College of Medicine in Cardiff. This was a rather superficial article which explained how the researchers tested the blood and saliva of over 400 pairs of siblings who were suffering from Alzheimer's Disease (AD). According to the article, the scientists compared the DNA of all of these samples and found that 64% of the patients who suffered from late onset Alzheimer's disease (LOAD) shared a common gene that can be found on chromosome 10, though its precise location is not yet known.
The article does a poor job of describing previous knowledge about the causes of Alzheimer's, failing to mention the APOE4 gene, which was integral as a comparison in the original study. Rather than informing the reader on what the study did, ie its methodology, and exactly what the researchers discovered, the author of this article concentrates on the future direction of this study and the miraculous cure to Alzheimer's that may eventually come from it.
BBC also fails to mention the 2 studies published in conjunction with the above paper, one of which, by Ertekin-Tanner et al., was important in reinforcing the conclusions arrived at by Owens et al..
Though the article does mention that several more genes are probably involved, it leads the reader to believe that this research has unearthed "a gene which could be responsible for the more common form of Alzheimer's disease." Admittedly, this line will catch the reader's attention, but if he was hoping to gain an insight on the exact discovery or the methods used to attain it, he will be disappointed.
Through this study, it has become quite obvious to me that one must read popular news articles with a cynical eye. This particular article is guilty of the most common omissions in popular science reporting: no discussion of the methodology implemented, change of the emphasis from the original paper, and overstating the most beneficial effects of the data. (Kua, et al., 2004) Science reporters have a tough job, however, in attempting to make a scientific paper understood by people who lack scientific training. While this article might contain sufficient information for most people, a scientist must know to take it with a grain of salt, and go directly to the original publication for more information.
BBC News. 2000 Dec 23. Alzheimer's gene discovery. BBC News. <http://news.bbc.co.uk/1/hi/wales/1081169.stm> Accessed 2004 September 1.
Ertekin-Taner, N. et al. 2000 Dec 22. Linkage of Plasma Aβ42 to a Quantitative Locus on Chromosome 10 in Late-Onset Alzheimer's Disease Pedigrees. Science 290: 2303-2304.
Kua, E., Reder M., Grossel M. 2004. Science in the news: a study of reporting genomics. Public Understanding of Science 13: 309-322.
McLean, Philip. 1998 May. Homepage. <http://www.ndsu.nodak.edu/instruct/mcclean/plsc431/linkage/linkage6.htm> Accessed 2004 September 10.
Owens, M. et al. 2000 December 22. Susceptibility Locus for Alzheimer's Disease on Chromosome 10. Science 290: 2304-2306.