. Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease. Hum Genet. 2001 Dec;109(6):646-52. PubMed.

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  1. Regarding John Hardy's quote at the recent German AD meeting (reported on by Kahle and DeStrooper) that it is a "fact" that the IDE gene on chromosome 10 is negative in association with AD, there is a danger to making such definitive statements based on case-control data on a handful of random individual SNPs in this gene. This presents a risk of prematurely dissuading investigators from studying a gene/protein that could provide important information on the pathobiology of AD. Most of the remaining late onset AD genes will likely have only modest to moderate effects, in terms of prevalence and penetrance, on overall risk for AD. Thus, testing only a few random SNPs in only three hundred or so case control samples (as John's consortium did for IDE) is clearly not sufficient to make definitive conclusions, positive or negative, regarding this gene's potential association with disease. With the availability of high quality, high-throughput genotyping techniques, a responsible geneticist is now obligated to test many evenly spaced SNPs (at least every ~ 5kB on average) chosen from as many linkage disequilibrium groups as possible. Moreover, both individual SNPs and SNP haplotypes must be tested (with corrections for multiple comparisons) preferably in thousands (not only a few hundred) of samples to provide definitive evidence for or against the involvement of a gene in AD pathogenesis. Until one does so, it would be most responsible to hold off from making definitive comments of "fact' one way or the other. Finally, comprehensive analysis of a candidate gene is best achieved by a consortium analyzing the same sets of SNPS in several large independent sample sets and comparing across studies. This has now been done for IDE and I look forward to John Hardy and his colleagues' comments and perhaps even follow-up analyses on those results when they are published. In summary, "facts" in genetics and science come about only after a sufficient number of independent analyses are carried out cross many labs. Until such facts are established and agreed upon, it is best for the field to keep an open mind about a very perplexing disease.

  2. I don't think this paper definitively rules IDE out as a LOAD gene. It simply says the authors could not find evidence for it in a case-control study of about 150 subjects with LOAD. It is not uncommon for different genetic methods to not confirm each other in the search for genes in complex, clinically and genetically heterogeneous disorders. So I would not say the paper negates the earlier work from Bertram et al., 2000.

    References:

    . Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science. 2000 Dec 22;290(5500):2302-3. PubMed.

    View all comments by Dennis Selkoe
  3. Authors' reply:
    In our study of IDE, we detected five SNPs in IDE occurring at >5 percent frequency, which we tested for association in a minimum sample of over 200 AD cases and 200 controls. Where there was a suggestion of a significant result for two of these SNPs, we tested a further 90-100 cases and100 controls. Our main rationale for testing IDE was that it maps to a linkage region for late-onset AD on chromosome 10. Our hypothesis was that if IDE explained the linkage, we would expect to find a risk allele, or alleles, conferring a relative risk of >3, i.e., a gene with an effect size comparable to that of ApoE.

    Not only did we fail to find any highly probable functional SNPs, but also, examination of our odds ratios (ORs) reveals that for all the SNPs we did detect, substantially smaller ORs can be excluded with 95 percent confidence from contributing even a fairly small genetic effect [IDE1 (203 cases/247 controls): OR 0.97 (95 percent CI 0.64-1.4); IDE2 (220 cases/245 controls): OR 0.94 (95 percent CI 0.69-1.3); IDE3 (224 cases/247 controls): OR 1.05 (95 percent CI 0.96-1.6); IDE4 (222 cases/248 controls): OR 0.97 (95 percent CI 0.970.73- 1.3); IDE5 (210cases/230 controls): OR 0.96 (95 percent CI 0.64-1.4)].

    We therefore conclude that it is extremely unlikely that variation within IDE is responsible for the linkage findings. We stated this conclusion in our paper "…our results indicate that this activity (of IDE) is unlikely to be important in influencing susceptibility to late-onset AD. As the approach taken has an 80 percent power to detect alleles of >3 percent frequency, we can conclude that coding sequence variants in IDE cannot be a significant risk factor for LOAD. Rare coding polymorphisms would not account for LOAD in more than a small proportion of the population and could not therefore account for our linkage data on chromosome 10…. ".

    Further, recognizing the strength of the functional data, we concluded that whatever these data say about IDE being involved in amyloid degradation, our findings suggest that genetic variation in the IDE gene does not greatly influence susceptibility to LOAD. "It remains possible that one or more of the SNPs we identified itself alters the expression of IDE or is linked to other variants that do, but that this has no influence on LOAD." This situation is directly analagous to that of BACE, where the functional activity of the b-secretase product against AβPP is clear, yet no genetic association has been established despite extensive analysis.

    We agree with Dr. Selkoe in so far as no study in science can ever exclude the possibility of a hypothesis, and that small genetic effects remain possible. However, in this case, our data overwhelmingly fail to reject the null hypothesis. The evidence published in support of IDE being a susceptibility gene for late-onset AD, which is based upon a microsatellite and was not confirmed in our dataset using the same marker, is comparatively weak. The balance of evidence is strongly in favor of the belief that IDE is not a susceptibility gene for AD.

    View all comments by Lesley Jones
  4. Reply to comment by Rudy Tanzi.
    Phillipp Kahle's and Bart De Strooper's comments on the Titisee Conference capture the flavor of the discussion on IDE (and other genes), especially between Steve Younkin and me. Deciding which other genes (besides ApoE) are involved in late-onset AD is difficult, and there are now many candidates, including A2M, IDE, ABCA1, for which some groups have reported positive data, but others have produced negative data. The biochemical and transgenic (IDE KO) data showing a role of IDE in Aβ biology is compelling; so far, our genetic data is negative (see ARF related news story) and I have not seen any published positive data. As always, however, the absence of evidence is not the evidence of absence, and I look forward to seeing Rudy's (and others’) data: It has been discussed for two years, and I have read press releases a couple of times, but the data remains unpublished. I would only point out that when the Duke group published their ApoE findings, we all knew they were right within three weeks.

    In addition, though, Rudy mischaracterizes our study: we actually measures linkage disequilibrium across IDE (substantial) and showed that no common haplotype was associated with disease. We did not assess "a few random SNP's." Of course our study, like all studies, is subject to limitations of statistical power and it remains possible that IDE is a gene of very small effect in late onset AD, or that very occasional mutations in IDE lead to recessive AD. Clearly though, our data rule out IDE being a gene of major effect for late onset AD.

    References:

    . Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease. Hum Genet. 2001 Dec;109(6):646-52. PubMed.