What is wrong with Alzheimer’s disease clinical research?
by Jack de la Torre, MD, PhD on 10 February 2017
There is increasing concern not only in Alzheimer’s disease (AD) research, but all of modern investigations, that false findings may be the majority or even the vast majority of published research claims .
Confidence in the findings of a scientific study depend, to a large extent, on establishing a reliable and accurate cause and effect relationship. Cause and effect is loosely defined as two events occurring in succession where the first event is considered the cause of the second event. This encyclopedic definition is often the deadly pitfall of countless scientific studies that contribute to false conclusions. The reason is that hypotheses that rely on cause and effect conclusions often ignore the post hoc ergo propter hoc fallacy, where one event spuriously correlates with another but is falsely deemed to have been caused by the related event. One way of lessening post hoc fallacies is by using causal reasoning. Causal reasoning is the process of questioning causality, for example, by carefully controlling the experimental findings to limit confounding factors or by observing that increased intensity of the presumed cause leads to increased magnitude of the effect.
But what happens when causal reasoning is abandoned in repetitive clinical trials testing the effectiveness of an intervention that consistently yields negative results? This has been the invariable fate of anti-amyloid-β (Aβ) drugs. These drugs were designed to eliminate excessive Aβ deposition in the brain of those afflicted with AD. The drug treatment rationale was based on the Aβ hypothesis, also known as the amyloid cascade hypothesis. This concept has been the prevailing but unproven paradigm in explaining AD causality for the last 20 years. Oddly, there have been more than 100 drugs tested in dozens of clinical trials and not one anti-Aβ drug has succeeded in slowing down AD destructive pathology or prevent declining cognition .
The multiple difficulties festering the Aβ hypothesis have been described in countless medical and scientific articles . One lethal blow to the Aβ hypothesis are the numerous clinicopathological studies revealing that heavy brain amyloid deposition does not equate with dementia . Most of the criticisms leveled at the Aβ hypothesis have been largely ignored by big pharma, its supporters, peer reviewers, and granting bodies as if no real challenge could lessen the power of this enduring paradigm. The best that can be said (to paraphrase big pharma executives) is that anti-Aβ therapy display ‘tolerability and safety’ when given to AD patients. But… so does chicken soup. How do any of these help stop the meltdown of AD?
Let’s play devil’s advocate for the sake of balance. What is wrong with pursuing a failed hypothesis? In the case of Aβ, it has provided jobs and resources for researchers who might not otherwise have had the financial capital to keep their labs open; moreover, such monies from big pharma to investigators could even uncover collateral information that could help clarify the process of neurodegeneration. On the other hand, ethical behavior may have been misplaced in this difficult time of financial hardship that threatens research survival.
However, it is unacceptable, in my judgment, when medical researchers (for whatever reasons) steadfastly hold onto a hypothesis that does not help sick patients in any manner despite being paid to do it. Rationalizing such behavior blocks medical progress resulting in dire consequences for the patients’ clinical outlook. Equally disturbing is the callous effect such conduct has on devaluing the scientific spirit and the search for truth.
A forward-looking concern is how to confront the monolithic and insular influence that Aβ research presently holds. Should a failed hypothesis continue to dominate funding research, publications, and conference programs while excluding other research ideas from the think tank? Such thinking requires a game plan whose main goal is not to stop all Aβ research but to open the think tank to other ideas and proposals that might benefit those at risk of dementia. This is a commendable task for graduate students and young investigators to pursue. The brilliant theoretical physicist, Max Planck, argued that scientific progress and evolution of thought does not advance because some inescapable truth is suddenly discovered that replaces the old and useless paradigm. Instead, Planck wrote in his autobiography, “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”
Let’s not wait for the opponents of new ideas that might replace the Aβ hypothesis to die; there is not much time for the millions facing an AD diagnosis and the agonizing death that follows.