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Failure of biomarkers in clinical trials of Alzheimer's disease: blaming the messenger?

Surrogate markers of disease activity have accelerated the development of treatments in diseases as diverse as HIV infection and multiple sclerosis, where viral load and brain MRI white matter lesion burden, respectively, have essentially replaced clinical outcomes for drug development. These are just two examples of the power of surrogate markers for testing therapeutic strategies for indolent diseases like Alzheimer’s disease (AD). Since a typical Phase III AD treatment trial based on conventional clinical outcome measures requires over 400 subjects followed for a minimum of 18 months at a cost of several million dollars, the possibility of conducting biomarker-based trials with a smaller number of subjects and shorter duration of treatment is highly attractive. The markers that have shown the most promise as trial outcome measures include MRI-derived brain atrophy rates [1], nuclear medicine studies of brain amyloid burden [2], and cerebrospinal fluid (CSF) levels of biochemical correlates of the classical AD lesions, namely amyloid-β42 (Aβ42) and tau [3]. Despite the modest