Only this type of morbidity data will provide the evidence base for continued use of the therapy. Second, we must find ways to ensure that the commercial sector will invest in prevention trials even if they take 10 or more years to complete. With huge investments

already made by the commercial sector in novel AD therapeutics, it will not take too many additional negative trials for the pharmaceutical industry to significantly reduce their investment in novel AD therapeutics. To ensure that we have the best possible therapies moving forward, we cannot afford to have the commercial sector largely abandon their efforts to develop novel AD therapeutics. The recent history of stroke therapeutics is highly informative in this regard. As highlighted in a recent review (O’Collins et al., Dabrafenib purchase 2006), out of 114 novel treatments tested in humans for stroke, only tissue plasminogen activator demonstrated sufficient efficacy and safety in human studies to be approved by the Food and Drug Administration. Because of this poor record of translation, efforts to develop

novel stroke therapies have been severely curtailed in the commercial LY294002 in vivo sector. The net effect of these negative trials is that the chances of developing novel breakthrough stroke therapies in the foreseeable not future have been significantly reduced.

The authors of that review on stroke therapeutics make several conclusions that are highly relevant to the AD field regarding alignment of preclinical studies and human clinical trials design. They suggest that some of the underlying factors that may have led to the high failure rate of stroke drugs are (1) limited preclinical assessment of many stroke therapies prior to human testing, (2) lack of alignment between the preclinical studies and the human trials and (3) overall lack of concordance between efficacy observed in preclinical models and clinical trial outcomes. As compared to stroke, where defining a homogenous intent-to-treat population is extremely challenging, in AD we may have the tools to identify a well-defined population with respect to AD-related pathology or lack thereof and also the capability to design preclinical studies that might more closely match the pathological state of those enrolled in the trial, at least with respect to amyloid burdens for anti-Aβ therapies. Thus, a third key step moving forward is to ensure that these kinds of alignments, when feasible, occur for investigative new drug approvals. By insisting that preclinical data and clinical trial design are aligned, the likelihood of translational success in novel AD therapeutics might be increased.