Alzheimer's therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond?

The worldwide incidence of Alzheimer's disease (AD) is increasing with estimates that 115 million individuals will have AD by 2050, creating an unsustainable healthcare challenge due to a lack of effective treatment options highlighted by multiple clinical failures of agents designed to reduce the brain amyloid burden considered synonymous with the disease. The amyloid hypothesis that has been the overarching focus of AD research efforts for more than two decades has been questioned in terms of its causality but has not been unequivocally disproven despite multiple clinical failures, This is due to issues related to the quality of compounds advanced to late stage clinical trials and the lack of validated biomarkers that allow the recruitment of AD patients into trials before they are at a sufficiently advanced stage in the disease where therapeutic intervention is deemed futile. Pursuit of a linear, reductionistic amyloidocentric approach to AD research, which some have compared to a religious faith, has resulted in other, equally plausible but as yet unvalidated AD hypotheses being underfunded leading to a disastrous roadblock in the search for urgently needed AD therapeutics. Genetic evidence supporting amyloid causality in AD is reviewed in the context of the clinical failures, and progress in tau-based and alternative approaches to AD, where an evolving modus operandi in biomedical research fosters excessive optimism and a preoccupation with unproven, and often ephemeral, biomarker/genome-based approaches that override transparency, objectivity and data-driven decision making, resulting in low probability environments where data are subordinate to self propagating hypotheses.