Commentary on "a roadmap for the prevention of dementia II: Leon Thal Symposium 2008." Prevention trials in persons at risk for dominantly inherited Alzheimer's disease: opportunities and challenges.

Autosomal dominant familial Alzheimer's disease (FAD) of young onset due to alterations in the PSEN1, APP, and PSEN2 genes is a fully-penetrant and devastating condition. As the subsequent development of AD in persons inheriting such genes is essentially certain, the condition provides a unique opportunity to perform informative studies of interventions with potential for preventing the disease. Though feasible, there are many challenges to such an endeavor including the fact that most persons at-risk for FAD do not desire to know their genetic status. Other challenges include the time course over which a preventative treatment would need to be administered and potential limitations to the degree to which the knowledge gained might be validly generalized to the more common late-onset AD. In this paper we discuss issues of study design including power estimates, protocols in which subjects' genetic status is not revealed to them, and the advantage of one-time interventions such as vaccinations. Though addressed in the context of FAD, many of the issues discussed are relevant to other fully-penetrant autosomal dominant degenerative illnesses such as Huntington's disease. We also discuss important next steps including the performance of pre-clinical studies in model systems appropriate for FAD and the recently funded international Dominantly Inherited Alzheimer Network (DIAN). The goals of the DIAN are to characterize the natural history of FAD and to establish the infrastructure that would be required to perform meaningful studies in this rare, widely dispersed, but informative population.