Questions With Panelists' Answers
Q: This is a question for John. Are there some kind of guidelines to publish or deposit genetics data so researchers like us know a high-quality dataset has been generated? Or who will control the quality of the database for the field?
John Hardy: Marc Cruts does a good job. His database is pretty much definitive. But you should always be careful, and if you’re really dependent on something—like a cell biologist working on a particular gene and mutation—then you really should (as Bart said) read critically the original papers and understand enough to know whether you can trust it.
Marc Cruts: I believe that it is extremely useful to get as many data on genetic variability of the disease genes available to the community as possible. Current publication standards have a discouraging effect on those trying to publish novel variations in known disease genes if they don’t bring essential novel insights into the biology. It is likely that there are many interesting variations in disease genes hidden in private laboratory databases of which we have no knowledge at all. This information would, for example, help identify neutral/protective variants or help develop criteria to evaluate pathogenic variations. Introducing strict publishing criteria for genetic data will have an even more negative effect, by which only the most obvious pathogenic variations get into the public domain.
What we do need are improved annotations of pathogenicity. We are working hard to improve the labels in the Alzheimer Disease & Frontotemporal Dementia Mutation Database, but as was obvious from the Webinar, this is a non-trivial issue. The decision trees presented by Rita Guerreiro are a good start toward that direction. However, for some variations, conclusive evidence will never be reached based on available evidence. For those variations, the original literature is the best resource to form a personal opinion.
Bart De Strooper: I agree that more data should become available in the public domain. It is generally true that the hurdles to publish repetitions of experiments and negative data or observations are quite high. Alternative ways of getting this knowledge on the Web would be very helpful. Could the database of Marc not be updated or linked to an online repository for short reports on such variants that include brief descriptions of clinical data and of the functional data obtained?
Q: What percentage of familial AD cases is not explained by mutations in APP, PS1, and PS2, and what is the frequency of ApoE4 in FAD cases, compared to sporadic AD cases and controls?
John Hardy: In my view, autosomal dominant disease (three generations, fully penetrant with reasonable onset age) is fully explained by APP, PSEN1, and PSEN2. On ApoE4, the percentage in “sporadic” European AD is about 36 percent, and in familial it is about 43 percent. I published on this a very long time ago. I would bet that others have, too.
Marc Cruts: We have still a few genetically unexplained autosomal dominant AD families. Unexplained "familial" AD patients are not exceptional.
Q: What do you make of the report in The New York Times quoting the main author of the recent Nature DECODE paper as saying that the APP variant protected all E4/E4 carriers in their study from developing AD?
John Hardy: I think it is probably correct (about 90 percent confident) that it is protective. I would hesitate to suggest it was 100 percent protective because the (n) is very small.
Comment: If two variants are found in the same patient, for example, one in PS1 and one in GRN, and that patient has a TDP-43 pathology, then I think using Occam's razor is a sensible approach; that is, the most simple explanation is the most likely. In this scenario, the GRN is clearly the pathogenic mutation, and a new function for PS1 causing TDP-43 pathology does not need to be invented.
John Hardy: I agree.
Marc Cruts: in general terms, carrying a pathogenic mutation in one gene does not protect one from having a second pathogenic mutation in another gene. Consequently, the presence of a probable pathogenic mutation in the one gene does not affect the probability of pathogenicity of the other mutation. The pathological and clinical picture can be modulated by both variations.