The lack of progress in the development of disease-modifying therapy in 
Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 
clinical trial studying the effects of bapineuzumab on mild to moderate disease. 
No treatment benefit was apparent, whereas several serious side effects occurred 
more commonly in the treatment group compared to placebo. This is the latest 
failure in a now long list of trials targeting lesional proteins believed to be 
fundamental drivers of the disease process. As the focus of the trial is 
directly tied to ostensible disease pathogenesis, objectivity compels us yet 
again to re-examine the amyloid cascade hypothesis as even a marginally 
significant pathogenic mediator of disease and to perhaps revert back to 
traditional science where repeated negative data leads one to consider other 
ideas. In the case of AD, amyloid-β metabolism and tau phosphorylation have been 
exhaustively studied, both to no avail. Oxidative stress has similarly been 
examined in detail by multiple mechanisms and targeted for treatment with a 
similar result. An appeal to the scientific community may be made to consider 
lesions in a different light. Have we been seduced by so-called hallmark lesions 
into believing that they are responsible for disease when in fact the reverse is 
true, and will we genuinely consider a systems biology approach to AD or instead 
continue on the path of the lesion, which has so far followed a flat line of 
progress?