Amyloid hypothesis' new dress
In 1906, Alois Alzheymer described the tangles and plaques, which define the neuropathology of Alzheymer's disease (AD). The question was whether the tangles and plaques caused AD, or they were a just a consequence of the disease.
More than one century later, the question still stands, as tall as ever, although somewhat skewed in its presentation. After the discovery of Amyloid-Beta and Tau proteins as the main components of the plaques and tangles, respectively, the investigation focused on the role of these proteins in AD.
The notion that Amyloid-Beta plaques caused AD, which has been labeled the amyloid hypothesis, has led most of the thinking and research in the AD field for more than a decade. However, many AD researchers have maintained that the amyloid hypothesis is flawed. It is important to emphasize that researchers on both sides of aisle have analyzed the same experimental data and observations. And, yet, their interpretation of this evidence is radically different, as driven by powerful scientific ideologies that would make even politicians envious. So much for the golden era of experimental biology!
Following the serial failures of the AD clinical trials, culminating with those reported in the article by Ewen Callaway (1), many scientists in the field thought that the amyloid hypothesis is dead (2, 3). Long live the amyloid hypothesis in its new clothes: it is the amyloid-Beta oligomers that cause AD, which means that the anti-amyloid clinical trials should start earlier, preferably before the accumulation of plaques.
Whether the amyloid hypothesis is worth the trust of the pharmaceutical industry and the US Government, which are footing the bill of hundreds of million dollars for the 3 AD clinical trials planned to start next year (1), should be open and fully addressed issue. And, it should be addressed before thousands of people implicated in these clinical trials, whether scientists, clinicians, or patients, put the hopes of their professional or actual life on the line.
Although, the support and participation of the sponsors, researchers, clinicians and patients in the new AD clinical trials should be highly appreciated, why trust the amyloid hypothesis, again? Maybe, because the desperation associated with this devastating disease is so great that ‘gambling’ becomes acceptable (4). Possibly, because there is too much academic capital invested in this hypothesis to abandon it now (3). Or, maybe, because the people involved in making the decisions about these clinical trials are not aware of alternative models about the etiology of AD that are more rational and make more sense clinically, biologically, and evolutionary than the amyloid hypothesis (5). Under no circumstances, however, should these clinical trials proceed because “we need to confirm or refute the amyloid hypothesis” (1); that work should be done before, not during the clinical trials.
Indeed, before starting these trials, it should be a professional, if not moral obligation for those directing these clinical trials, as well as for all researchers in the AD field, to engage in an open and thorough evaluation of the current hypotheses on the etiology of AD. The costs for this analysis would be negligible, and the potential benefits extraordinarily. And, hopefully, this evaluation will also prevent, a few years down the road, the cry that the amyloid hypothesis has no clothes and it needs to be dressed again!
References
1. Callaway E. Alzheimer’s drugs take a new tack. Nature 489:13â€ऴ, 2012.
2. Editorial. The amyloid cascade hypothesis has misled the pharmaceutical industry. Biochem Soc Trans. 39:920-3, 2011; (http://www.ncbi.nlm.nih.gov/pubmed/21787324.
3. Castellani RJ, Smith MA. Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail’. J Pathol. 224:147-52, 2011; (http://www.ncbi.nlm.nih.gov/pubmed/21557219.
4. Marchesi VT. Alzheimer's disease 2012: the great amyloid gamble. Am J Pathol. 180:1762-7, 2012; (http://www.ncbi.nlm.nih.gov/pubmed/22472273.
5. Bandea C. Alzforum Current Hypotheses: AD, PD, HD, ALS, FTLD-U, CJD and RSA are autoimmune disorders: a unifying hypothesis on the function of Amyloid-Beta, Tau, Alpha-Synuclein, Huntingtin, TDP-43, PrP and AA in innate immunity. 2011; (http://www.alzforum.org/res/adh/cur/bandea/default.asp
