, 2008 and Das

et al., 2001). Thus, it is uncertain whether efficacy with respect to alleviating the behavioral changes observed in such mouse models, especially performed in preplaque stages, would be able to predict efficacy with respect to behavioral alterations in humans with symptomatic Sirolimus mouse AD. There are two straightforward ways to solve the dilemma through medical and scientific progress. First, with anti-Aβ therapies and perhaps anti-tau therapies, we should conduct primary prevention or intervention trials in minimally affected individuals (secondary prevention in stage 1/2). A second, alternative, strategy would be to develop therapies more likely to work in symptomatic patients (i.e., in a preclinical stage 3 or prodromal Obeticholic Acid chemical structure AD). When considering primary prevention or very early intervention in asymptomatic subjects, the key scientific issue will be whether a therapy can be developed that hits the target sufficiently to have a very good chance for disease modification and is sufficiently safe for use in people included in the trial but not destined to develop AD or likely to develop the clinically symptomatic illness only after several years of good health. Whether a candidate drug can be considered sufficiently safe will depend on (1) the underlying

biology of the target (mechanism-based toxicity), (2) the ability to avoid off-target effects, and (3) an empirically determined assessment of benefit versus liabilities. Whether a therapy is safe enough will also be influenced by the conditions of use, whether one is considering a true primary prevention trial, a trial in preclinical AD, or a trial in established second symptomatic AD, as the risk to benefit profile will shift toward tolerating greater risk with advancing

clinical disease. In the later populations, the bar for safe enough is lower given the evidence for irreversible though protracted progression. Many current anti-Aβ therapeutic modalities fail the safe enough test even in symptomatic patients, especially given the long-term treatment that is necessary in this chronic condition. However, a number of modalities, such as selective γ-secretase inhibitors, γ-secretase modulators, and second or third generation vaccines, theoretically hold some promise for meeting the safe enough requirement for testing as prophylactic agent (Golde et al., 2010). From a medical perspective, a key issue will be whether the community will accept the concept of presymptomatic AD, which, to reiterate, is the presence of Aβ aggregate accumulation with or without some evidence for neurodegeneration in the absence of detectible cognitive symptoms. This diagnostic construct is invaluable when considering moving toward primary prevention or early intervention trials as it potentially identifies the earliest manifestation of the disease.