But, if tested in a primary prevention or early intervention trial, the therapy might show remarkable efficacy. Clearly, no one wants this very plausible hypothetical situation to become reality. In order to prevent this from happening we outline some of the key next steps. First, we must continue the funding of studies that are needed to prove biomarkers can be used as endpoints

and represent truly valid clinical surrogate endpoints. Given the cost and risks associated with developing drugs for prevention of AD, it is likely that the development process will need to be staged and all phases of the approach linked to biomarkers. In the first stage, premorbid biomarkers for the pathology of AD would be used to select patients or enrich a sample for likelihood of progression Ulixertinib order find more to AD in

a reasonable time-frame. Examples of premorbid biomarkers for primary prevention studies might be those based on APOE genotype alone or more extended genotypes that might emerge from ongoing genome-wide association studies. For secondary prevention studies, one might consider diagnostic biomarkers such as CSF Aβ, tau, or both or imaging studies such as FDG-PET profile, brain amyloid load, or hippocampal or medial temporal lobe volume. In either case, more than one biomarker may be needed to better identify an asymptomatic risk state or preclinical AD that is currently defined only as a biomarker positive risk state. In the second stage, biomarkers will be needed to demonstrate that the therapy is appropriately modifying the target. For example, with an anti-Aβ antibody-based therapy, a decrease in brain amyloid tracer

retention with an Aβ antibody therapy would indicate target engagement and thereby justify further trials. In the third stage, biomarkers might be used as surrogate endpoints. In a primary prevention trial, the endpoint might be time to conversion to a stage 1 biomarker or, for a secondary prevention trial, time to conversion of a stage 2 biomarker. Dichloromethane dehalogenase Although biomarker-based trials can add substantial costs on a per subject basis to the trial, these costs might be offset partially or wholly by possible reductions in length of trial, reductions in sample size needed, or both. Development of plasma-based biomarkers that predict preclinical stages of AD could considerably reduce the cost of a biomarker-based prevention trial, making it much more feasible from an economic point of view. However, despite intensive efforts, even state-dependent diagnostic plasma biomarkers that reliably distinguish AD patients from controls have yet to be developed. In any case, the knowledge-based, regulatory, and legal issues involved in using both validated and novel surrogate biomarkers for AD trials are substantial and require detailed consideration ( Katz, 2004). A biomarker-based approach to AD prevention or early intervention trials will probably increase the costs associated with the trial and is not without inherent risk.