The article discussed today is a more philosophic one, as there are currently few research news in our field.
Frustratingly it starts great but quickly loses its way. This article is quite representative of a current wave of attacks on the pragmatic aspect of medicine by scientists frustrated by their lack of progress. As they say in Silicon valley "Fake it till you make it".
The authors are indeed right that drug discovery in neurodegenerative diseases is currently in a conceptual crisis. A clear illustration of this can be seen in hundreds of failed clinical trials of Alzheimer’s disease, ALS, vascular dementia, dementia with Lewy bodies, and Parkinson’s disease dementia, despite countless hypotheses on possible mechanisms.
To date, we have accumulated many negative randomized clinicals in these diseases. These results have not prompted a major reconsideration of the toxic proteinopathy hypothesis of causality. Imperfections in trial design and execution (incorrect dosage, insensitive endpoints, too-advanced population) but not in the underlying hypotheses have prevailed as explaining the failures. Surprisingly, the huge cost of these trials has not interrogated the managers of the pharmacological industry.
Many existing drug development programs for those diseases have been based on the “proteinopathy” concept, whereby proteins in a misfolded aggregated state cause the disease. As a consequence, it is understood that removing them from the brain should cure these diseases.
The cumulative lessons of more than 40 anti-Aβ Alzheimer’s trials should have taught us otherwise: 15 monoclonal anti-amyloid antibodies significantly reduced amyloid and, surprisingly, significantly worsened patients’ outcomes compared to placebo. Yet none of these trials was interpreted as a rejection of the hypothesis. Instead, the anti-amyloid antibodies, lecanemab and donanemab , which met the statistical threshold in the opposite direction, have been taken as a confirmation of the hypothesis, although they never translated into clinically relevant benefits.
Instead, reduction in soluble Aβ levels, as measured in cerebrospinal fluid, is harmful to humans, and removal of insoluble Aβ may lead to microhemorrhages, brain atrophy, and death. The toxic Aβ hypothesis has become virtually unfalsifiable. Moreso, scientists now propose to define and diagnose these diseases by molecular biomarkers. This means that any drug that can reduce those diagnostic biomarkers (and many can) must be authorized by the FDA!
Collective evidence should have sufficed to consider amyloid rather as a downstream consequence in cellular pathophysiology, a sign of a range of biological stressors, not their cause.
The scientists call for a move from the current medical methods towards a divergent, organ-agnostic, and mechanism-based disease nosology (the branch of medical science that deals with the classification of diseases).
They complain that the focus has always been on the brain. This brain-centric approach has been maintained by the majority of clinicians and researchers to date. Yet a single pathology in the brain is the exception rather than the rule. In clinical practice very rarely do doctors find patients with only dementia or only metabolic, sensorial, or motor symptoms.
Real-world aging individuals, with or without neurodegenerative disease, have mixed manifestations of biomarkers in their brains, with almost 80% of these individuals presenting with at least two of such neuropathologies.
In contrast with the model of brain-centricity, these “dementia specific” markers can be often found in organs outside the brain, for example, Aβ aggregates documented in the skin, intestines heart, and pancreas. This should not surprise us, all cells in our body share the same DNA, and most cellular receptors are not specific to a single organ.
The authors are in favor of "network medicine". Network medicine is the application of bioinformatics concepts towards identifying, preventing, and treating diseases. It focuses on using network topology and network dynamics to identify diseases and develop medical drugs. Disease networks, which map relationships between diseases and biological factors, also play an important role in the field.
Sadly but in line with this network medicine approach the authors propose a new way to characterize diseases that is the current proposed way with just another name. The authors propose to use endotypes, but endotypes are synonymous with biomarkers!
They curiously use an example of the failure of their own "modern" approach to promote it: They recall the recent accelerated approval of the anti-amyloid monoclonal antibodies aducanumab and lecanemab by the US Food and Drug Administration became the culmination of this paradigm, despite the failure of their clinical trials.
Revising disease and drug concepts
They also propose to use the concept of disease module instead of phenotype (observable characteristic or trait of a disease) to classify and name diseases. For the authors, disease modules are rather small localized multi-protein signaling networks, typically distinct from curated canonical signaling pathways. As not two scientists can agree on subtle pathways or bioinformatics networks, good luck to those tasked to define disease modules.
The authors do not stop there, they also want to change the meaning of the word "drug". For them, as the current drugs are inefficacious, we must accept no drugs approach such as lifestyle interventions.
In another publication, the authors attack the clinical trial's current way of interpreting results and propose a minimal set of rules that facilitate the interpretation of negative clinical trials as falsifying the driving hypotheses, in particular, if the desirable change in surrogate endpoints has been achieved.
It's not clear why the authors wrote this article, it does not create new knowledge, instead, it's a semantic play on existing concepts.
As for “network medicine”, it remains to be seen whether it will provide a solid framework and pragmatic results in the future, or whether it only constitutes a high-tech version of another alternative medicine.