, 1997 and Reiman et al., 2010). Simple genetic screening could theoretically provide cohorts for selection of trial participants with this geneotype. However, the low frequency of homozygous APOE ɛ4 carriers severely limits their recruitment and possibly even generalizability to the population as a whole. Choosing such samples as familial early SCH772984 onset AD or people who are homozygous APOE ɛ4 carriers as the intent-to-treat population also raises another issue, which is whether the expected action of the drug is influenced by the genetic makeup of the individuals. For example, presenilin-linked AD is associated with

altered Aβ42 production ( Selkoe, 2001), while APOE ɛ4 is associated with decreased clearance of Aβ from the brain ( Holtzman et al., 2000). APOE ɛ4 heterozygotes are another at-risk potential sample for prevention trials: these individuals constitute approximately 24%–30% of the population, have three times the risk for AD, about a 10 year lower age-of-onset compared

to APOE ɛ3 or ɛ2 carriers ( Farrer et al., 1997), and represent ∼50% of AD cases ( Roses, 1997). Although they have one-fifth the risk for AD compared to ɛ4 homozygotes, they are more than eight times easier to recruit by virtue of their Crizotinib supplier prevalence. Thus, a prevention trial with heterozygotes may be carried out efficiently and be more generalizable to the majority of AD patients. In many scenarios, a 15–20 year timeline would be the minimum time to test, possibly retest, and widely deploy an effective true primary prevention therapy or a therapy for the clearly asymptomatic preclinical stages of AD. In the interval, millions of people will continue to develop AD. So what do we do for them? First, we can simply hope that the predictions of the cascade hypothesis are wrong and that trigger-targeting therapy will show

better efficacy in current trials than might be predicted. Evidence for efficacy and safety would probably mean much more rapid approval for symptomatic use. Second, we can renew our ALOX15 efforts to identify novel downstream targets and develop novel neuroprotective or regenerative therapies that may be more efficacious than targeting upstream pathways in true treatment trials. These studies would be greatly facilitated by the development of animal models that recapitulate the full disease phenotype. An important area where the medical and scientific field can improve in order to overcome the treatment versus prevention dilemma is to better align the design of preclinical studies with subsequent clinical trial designs. This means that the usual chronic dosing studies in pre- or early amyloid-depositing APP transgenic mice with anti-Aβ therapy must be accompanied or replaced by studies in which the mice have AD-like Aβ loads at the time the treatment is initiated.