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.”

Silver staining techniques and Congo red birefringence [5,6] were the mainstay of amyloid plaque analysis until the small protein Aβ, a metabolic product of AβPP transcribed on chromosome 21, was found to be the major component [7,8]. During this time period, a conspicuous shift from the notion that senile plaques are an accompaniment of disease, to plaques being directly tied to etiology and pathogenesis [9–12] occurred. The identification of kindreds of familial AD linked AβPP germline mutations, as well as the development of neuropathology in cases of Down's syndrome, in which patients have an extra copy of AβPP, reinforced this notion.

While the genetic mutations involving AβPP, presenilin (PS), and trisomy 21 result in an AD-like phenotype, it is important to remember that the total identified familial early-onset AD kindreds with known mutations number only about 450. Clinical presentation in familial disease is also heterogeneous and can present with cerebral hemorrhage without dementia, spastic paraparesis with delayed dementia, subcortical dementia with Parkinsonism, and seizures [13–15] – clearly differing from sporadic AD. Also different from sporadic AD are the extensive Aβ burden often throughout the white matter, deep gray matter, cerebellum, and “cotton wool” plaques that lack fibrillar Aβ as in PS1 mutation cases, such that early-onset familial AD imperfectly mimics the far more common sporadic condition.

The cohort of dementia subjects number at least 20 million across the globe. Moreover, in sporadic disease, a variety of other specific risk factors come into play (e.g., head trauma, diet, sex hormones, educational background, and aluminum exposure) [13], which are unaccounted for by simplistic reductionist theories.

Aβ has been shown to be toxic in vitro by a variety of mechanisms, including induction of apoptosis [30], promotion of inflammatory mediators [31], and as an accelerant of oxidative stress [32]. Many in the field realize the technical difficulties when working with amyloid protein and peptide fragments. The variation of fragmentation, insolubility, and self-assembly proficiency are some of the issues, as are reproducibility inconsistencies due to concentration, pH, or different effects in in vivo versus in vitro studies. The ratio of the various cleavage products is one of intense scrutiny. Even if you disregard the notion presented earlier that AβPP processing is a host response, the variability and different ramifications reported for amyloid fragments and their ratios merits discussion. Not all studies conclude with or promote the idea amyloid toxicity. In a large epidemiological analysis using pooled data from many studies, non-steroidal anti-inflammatory drug (NSAID) use was shown to reduce the risk of AD. Another variable in this group was the further identification of use of NSAIDs that specifically reduce Aβ_1–42, called selective Aβ₄₂-lowering agents. Neither this class of NSAIDs nor aspirin alone had any additional advantage for the protective effect seen [33]. Aβ_1–40 has been shown to be protective, thus targeting Aβ₄₀ formation pharmacologically, or immunologically, could be deleterious [34]. When mice specifically bred for overexpression of Aβ_1–40 were crossed with both the Tg2576 mouse model as well as mice specifically overexpressing Aβ_1–42, the overall higher levels of Aβ_1–40 inhibited amyloid deposition by 60–90%. Soluble Aβ₂₈ has proven antioxidant properties and readily chelates metals, albeit not efficiently [35]. Increased redox-active metal accumulation is a feature of amyloid plaques and is likely a result of mitochondria dysfunction. Therefore, neuronal survival mechanisms in which soluble AβPP fragments promote neurogenesis, and in which some Aβ fragments confer antioxidant or protective properties may be driving the equilibrium toward increased AβPP processing. The byproduct, amyloid aggregation, is a further protective response to protect cells from the rather toxic protofibrils or oligomers. Targeting AβPP processing therefore will not protect neurons, unless an underlying cause responsible for the increased AβPP expression is determined.