In EOAD, the heritability is higher and culprit genes have been i

In EOAD, the heritability is higher and culprit genes have been identified. Mutations in three genes account for 11% of the genetic causes, and this genetic load is markedly higher than that of the susceptibility genes in LOAD. In LOAD, causative genes have not been identified, and the strongest risk allele is the APOE4 (apolipoprotein E) allele, conferring in the Caucasian population odds ratios of 10 to 14 in homozygotes and around 3 in heterozygotes [40]. Furthermore, incorporating EOAD cases may introduce subjects with mutations in APP, PSEN1, and PSEN2. As most animal models for AD involve mutations in one or a combination of these genes [41], preclinical testing is performed on transgenic animals that in fact model the pathomechanism responsible for AD in this subset of patients.

This group would be the ideal cohort for proof-of-principle studies for amyloid targeted therapies, but this is unfortunately precluded by the rarity of mutation carriers. On the other hand, there is no compelling argument in favor of excluding genetic cases, even from trials assessing the efficacy of therapies with a non-amyloid target. Clinical trial design is regulated and guidelines for the design of clinical trials for AD were published by the European Medicines Agency (EMEA) [42] and draft guidelines are available in the US and other countries. These guidelines do not mention early-onset or genetic AD as an exclusion criterion. Thus, from a regulatory point of view, there is no reason not to include these patients.

The age range for current clinical trials is variable, with age 55, 60, or 65 years often used as the lower limit cutoff for enrollment. As the definition of EOAD is onset at less than 65 years of age, EOAD cases are already enrolled into clinical trials. The EOAD subset that is currently excluded likely represents less than 1% Anacetrapib of all AD cases and includes the majority of the autosomal dominant cases. The conundrum is that we use transgenic animal models based on the amyloid hypothesis to test compounds for efficacy, and subsequently we exclude the patients whose pathomechanism is closest to the model organism, in which it is most likely that the observed effect is replicated. Furthermore, if this 1% were to enroll in clinical trials, they would be randomly assigned, like all patients, to drug or placebo and could not substantially alter the outcome of the trial, even if they had a differential response to the treatment.

Concerns about a differential safety profile in autosomal dominant EOAD have been raised. As the validity of these concerns are uncertain, safety related to genetic status should be managed in trial design by addressing it in the monitoring procedure and Calcitriol manufacturer subgroup analysis for the EOAD subset. Finally, careful consideration of the ethical aspects of exclusion of EOAD patients is warranted.

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