Should persons with autosomal dominant AD be included in clinical trials?

We agree with the authors that SAD cases under age 65 should be included in AD trials. The literature describing these cases does not suggest that clinical or biological differences warrant exclusion. We take pause, however, with the recommendation of categorical enrollment of ADAD patients in trials. Inclusion of persons with ADAD should be dependent upon the nature of the causative mutation, the drug under investigation, and the study objectives. More than 200 AD-causing mutations are known, and predicting the impact of all disease-causing mutations on drug efficacy is difficult. APP mutations are most frequent in the β- and γ-secretase cleavage regions and result in increases in the levels of both Aβ42 and Aβ40, Aβ42 alone, or the ratio of Aβ42 to Aβ40 [2,3]. Aβ40 resultant from processing of mutated APP is resistant to degradation by neprilysin [4,5]. γ-Secretase inhibitors may lack efficacy in preventing APP cleavage by enzymes resultant from mutated PSEN genes [6,7]. On pathological examination, the brains of persons with ADAD can demonstrate atypical morphology, distribution, and composition of Aβ deposits [2]. Biological differences between ADAD and SAD might manifest similar differences in response or side-effect profile to a given intervention and thus should be considered care fully before patients with ADAD are enrolled in trials.In phase I studies, biological differences between ADAD and SAD could translate to different dose requirements since younger patients with ADAD are likely to have a more rapid drug metabolism. Females may also be premenopausal, making teratogenicity a consideration. In phase II, differences in ADAD could have effects on outcomes and interpretation since ADAD participants might be overrepresented, given that the percentage of SAD patients who qualify for trials is low, ADAD patients have fewer barriers to participation, and trials are often conducted at academic centers where ADAD is studied. Alternatively, persons with ADAD migh