Reviews of the molecular pathogenesis of Alzheimer's disease (AD) tend to invite the reductionist approach to disease. Indeed, it is now customary in some circles to begin reviews, discussions, and lectures on AD with a schematic diagram of the amyloid-β protein precursor (AβPP) molecule, implying that this molecule encapsulates AD so completely that the disease itself is almost of secondary importance.
Such a mindset tends to ignore not only competing reductionist theories, but the complexity of chronic diseases in general. Moreover, referring to any one approach as “once controversial” highlights the magnitude of the problem, and the necessity to return to objective review of data that are generally soft and manipulable. In effect, how many patients need suffer an untimely demise at the hands of clinical trials driven by schools of thought that are no longer controversial, before a paradigm shift occurs?
This mindset tends further to lend a theological tone to pursuit of scientific data and thus invite not only a more objective assessment, but outright cynicism [1
]. It may well be, however, that a return to objectivity, and indeed cynicism, are long overdue. Of the numerous hypotheses, none have resulted in a tangible treatment benefit, whereas millions would proffer themselves and their family members as guinea pigs, purely out of desperation.
Such is a clarion call to medical ethicists. Life is often eagerly risked in exchange for a mere modicum of hope because of what otherwise awaits the afflicted. At the same time, much more than a modicum of hope is all too palpable and equally unjustified, in even a cursory review of the scientific literature. Such a combination is a blueprint for exploitation.
Perhaps more disturbing are the schematic diagrams and modern graphics (i.e., cartoons) that demonstrate hypotheses in the mainstream press, which in effect give the “lay person” the illusion of understanding and the academic the illusion of progress, exacerbating the underlying problem. Titles and university affiliations decorate the work and provide unassailable credibility, while the entire package is sold like an elixir in the marketplace of public thought, as the waters of human suffering are trolled, intentional or not, for the afflicted and their families.
Realistically speaking, the perversion of the scientific method, and manipulation of a desperate public afflicted by an expanding, devastating, and incurable disease, characterize AD research and treatment in the 21st century; nevertheless, the peer review processes, the competition for public funds, and the embedded centers of opinion continue, unabated and unabashed, as knowledge of epiphenomena expands and progress toward effective treatment stagnates.
Pathological interpretation of neurodegenerative diseases has, for better or worse, focused on proteinaceous inclusions for no other reason than the fact that they can be visualized. Yet, implicit in the vast majority of studies on disease pathogenesis is the assumption that these lesions themselves are inherently toxic, and therefore represent disease per se rather than disease response. Such a conclusion is clear from the frenzy of studies that followed the identification of amyloid-β (Aβ) and tau in their respective lesions. Remarkably, in 2009, after nearly a quarter century of lesion primacy, and after targeting of Aβ as an avenue of treatment has repeated failed, the amyloid cascade concept is referred as “once controversial.”
Here we will scrutinize the findings that 1) advanced protein aggregation, in addition to serving protective functions in other tissues, may protect cells from toxic intermediates; 2) amyloid protein fragments have antioxidant properties; 3) protein modifications upstream of AβPP processing affect plaque formation and promote neurogenesis; and 4) treatments that specifically target amyloid do not affect disease prevalence nor progression. Overall, based on these data, we propose that Aβ is not responsible for the clinical manifestations of AD.