Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress

Arch Med Res. 2012 Nov;43(8):694-8. doi: 10.1016/j.arcmed.2012.09.009. Epub 2012 Oct 16.


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?

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / metabolism
  • Amyloidosis / metabolism
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Energy Metabolism
  • Humans
  • Mitochondria / metabolism
  • Models, Neurological*
  • Oxidative Stress
  • Phosphorylation
  • Systems Biology / trends
  • Treatment Failure
  • tau Proteins / metabolism


  • Antibodies, Monoclonal, Humanized
  • tau Proteins
  • bapineuzumab