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  1. This is a great project. The idea of looking at protective rather than risk factors is attractive because it has direct potential to result in preventative therapies. It is the extreme version of looking at patients at the ends of the spectrum, but in this case the individuals did not even develop disease.

    There are no doubt challenges to this approach. They will likely only identify very few individuals with mutations in a particular gene, and it will be challenging to determine what it is that protects them. Genetic, epigenetic, and/or environmental factors may all play a role. If they are lucky, and the same factor protects a subset of patients with a particular mutation, it should work.

    There is definitely a possibility of using a similar approach to study dementia-related genes. Carriers of the C9ORF72 repeat expansions have been reported in about 1 to 2 per 1,000 healthy older individuals. Although these individuals may still develop symptoms at a later age, it is worth studying them and comparing them with those who develop disease in their 30s. Our work on the TMEM106B gene also showed that mutations in progranulin (GRN), initially thought to be nearly fully penetrant, can in fact occur in healthy individuals protected by the TMEM106B gene. I strongly believe that secondary mutations and environmental factors play an important role in the disease presentation of C9ORF72 and GRN mutation carriers, and we and others are collecting large series of individuals with these mutations in an attempt to identify such genetic modifying factors.

    In the future I could see similar initiatives being launched for other disease including dementia. The collection of large series of healthy ApoE4 homozygous carriers is particularly attractive and may be even more feasible than the resilience project as the frequency of e4 carriers in the general population is much higher.

    View all comments by Rosa Rademakers

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  1. Resilience Project to Uncover Why Some Mutation Carriers Stay Well