Scientists are never short of new hypotheses about the cause and even the nature of diseases. For example, some of them now believe that “inflammation” is the underlying cause of many neurodegenerative diseases.

The human immune system is made up of different subsets of extreme complexity. The main mode of action is quite brutal, as the cells renew themselves quite quickly (from a few days to a few weeks), any slightly suspicious cell is deliberately killed by one of the agents of the immune system.

The central nervous system is composed of cells that have a probable lifespan of a hundred years or more, and they do not renew themselves through division, so this mode of operation is impossible. Therefore the central nervous system is kept isolated from the rest of the body through the blood-brain barrier and it has its own immune system.

Breaks in this barrier and the invasion of the CNS by the body's immune cells have sometimes been suggested as being able to cause diseases such as ALS, and now Alzheimer's. A new article aims to show that in the case of Zika viruses, the terrible consequences that an infection causes are not due to the infection of cells by the virus, but by the invasion of the CNS by immune cells from the rest of the body.

The article incriminates CD8+ T cells which function like NK cells, formidable killers.

Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis.

Of course, this article is based on an experiment with mouse models of a disease, so it is quite risky to draw conclusions for humans.

In any case, once the damage is done, it is too late, as the neurons do not reproduce. Yet it is possible to have a form of damage mitigation, either thanks to neurogenesis in certain rare cases, or even to a sort of mutual aid mechanism between neurons, which causes a surviving neuron to try to take over the work of the dead neurons. This is what causes us to become clumsy as we age.

Therapy is therefore not to be expected quickly, the best is to maintain a healthy blood-brain barrier, that is to say, to follow the precautions recommended for cardiovascular diseases.

The TCA cycle (Krebs cycle) is the primary mechanism for ATP synthesis in brain cells, operating within the mitochondria's matrix. Additionally, glycolysis contributes to ATP production, particularly during heightened energy demands or glucose scarcity. Insulin plays a crucial role in regulating glucose metabolism and maintaining neuronal function.

Mitochondria, akin to tiny microbe-like structures, are strategically located within cells to provide energy where needed, including neuronal terminals. Synthesized primarily in the soma, the central part of the neuron, mitochondria must undergo transport to distant neuronal terminals. Maintenance of mitochondrial health is crucial as damaged mitochondria can induce oxidative stress, necessitating fusion with healthy counterparts for repair or elimination. Thus, ensuring mitochondrial integrity is paramount for neuronal function.

In both processes -glycolysis and the citric acid cycle- during oxidative phosphorylation (OXPHOS) glucose and other substrates are metabolized, generating the synthesis of ATP.

A new text using the detrimental effects of S-nitrosylation on TCA cycle function, provides insights into potential therapeutic interventions.

The scientists compared in-vitro isogenic wild-type and Alzheimer's disease mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN) and found evidence of dysfunctional processes in mitochondria. This aberrant S-nitrosylation is documented not only in hiN cells but also in postmortem human Alzheimer's disease brains versus controls

Detailed analyses showed significant inhibition of metabolic flux at various steps of the TCA cycle in hiN. It suggests that deficiencies in TCA cycle function were associated with a shift towards compensatory glycolysis, suggesting an adaptive response to impaired oxidative phosphorylation. In particular, supplementation with dimethyl succinate, a substrate bypassing the inhibited step in the TCA cycle, suggests a potential therapeutic strategy to mitigate mitochondrial dysfunction in Alzheimer's disease. Dimethyl succinate (DMS), a membrane-permeant form of succinate, could serve as a pro-drug to provide substrate to the next enzymatic step in the TCA cycle, succinate dehydrogenase (SDH).

Those findings are not entirely surprising and the motivation of the scientists seems more to test a new mass spectroscopy technique than finding a drug. Anyway, it may add to the incentive to make pre-clinical trials of dimethyl succinate in rat Alzheimer's disease models.

Usually, Dimethyl succinate is sometimes used as a solvent. Yet dimethyl succinate is an irritant and an explosive product.

Unfortunately, after decades of research and hundreds of unsuccessful phase III clinical trials, it's clear that the pharmacological industry and a cohort of academic laboratories are unable to create drugs that slow significantly the progression of neurodegenerative diseases.

Some courageous scientists interrogate basic hypotheses or design longer, more complex better clinical trials. For example, Alzheimer's disease can't seriously be attributed to any molecular dysfunction, as it would mean that a lot of cerebral functions would be affected, not only memory issues, and anyway, memory issues in Alzheimer's are much more complex than described in textbooks: They did not simply vanish: The patient looks to be living today in the context of the past. Sometimes the patient can discuss simultaneously at two levels: In the context of the past (when they were infants) and in the context of today.

Others are currently busy breaking the thermometer. If the clinical diagnosis makes it impossible to validate current clinical trials, then change the way success is defined: Abandon clinical criteria and use molecular criteria. They did it recently for Alzheimer's disease and now they propose it for Parkinson's disease..

The immediate consequence will be a flurry of successful clinical trials, even if patients get no improvements, as they did for Aducanumab.

There will also be false positives, people will be diagnosed sick because of the presence of a molecule but without any clinical signs.

Quelques jours avant que mon père décède, j'ai demandé à son médecin quelles pouvaient être les actions médicales à mener pour améliorer son état. Le médecin m'a répondu "si on arrive à améliorer ses constantes, il ira mieux".

Outre le fait que le médecin ne me répondait pas vraiment en terme d'actions à mener, cette lapalissade enseigne quelque chose de fondamental au sujet de l'approche de la santé par la médecine.

Les médecins sont conscients qu'en fait ils ne peuvent peuvent pas vraiment soigner, ils ne peuvent qu'améliorer un dysfonctionnement d'un corps qui autrement doit être en bonne santé. Ce corps, si on l'aide, va retrouver sa bonne santé.

Au contraire, une personne atteinte de comorbiditées a une chance de survie très faible, c'est de la statistique élémentaire. Si un malade a trois problèmes de santé ayant chacun une chance de survie de l'ordre de 80%, la résultante n'est que de 51%. Il est donc illusoire de penser que quand la physiologie est sévèrement compromise, on pourra restituer la santé avec une pilule ou une injection miracle.

Cette limitation de la médecine actuelle, n'est pas compris par les scientifiques. Ceux-ci s'obstinent à penser qu'en agissant sur une composante infinitésimale de notre physiologie, la santé sera, comme par magie, restituée. Cet aveuglement s'explique par le fait que la quasi totalité des scientifiques oeuvrant dans la recherche médicale, n'ont qu'une notion vague de la physiologie humaine et des interactions entre ses multiples systèmes.

Cela explique pourquoi je ne présente pas les multiples articles qui apparaissent tous les jours et qui annoncent une découverte majeure, alors que le plus souvent il s'agit de travaux mineures sur une souris, ou pire encore sur une lignée de cellules dénaturées immortelles.

Outre le fait qu'un scientifique doit publier pour être crédible, et donc qu'on a une avalanche de papiers au style ampoulé mais sans valeur, beaucoup se demandent pourquoi les souris semblent si bien répondre aux traitements, alors que quand ces traitements sont testés sur des humains, ils échouent à améliorer l'état des malades.

La réponse est complexe, mais un point essentiel est celui-ci: La tenue de l'expérience est soit confiée à des étudiants (masters, doctorants), des salariés (postdocs) ou à un organisme de sous-traitance de la recherche (CRO). Dans ces différents cas de figure, les personnes à qui sont confiées ces souris ont intérêt à ce que l'hypothèse faite par le professeur donneur d'ordre soit avérée. or on sait que la santé d'une souris est fortement dépendante à des caresses ou à un nettoyage de la litière (ce qui d'ailleurs influence le microbiome intestinal)...

La moralité de tout ceci est que pour un patient il faut essayer de faire fonctionner normalement son corps et son esprit autant que possible: Conserver une certaine activité physique, conserver une activité intellectuelle, s'informer à des sources fiables, avoir une sécurité financière, combattre les problèmes cardio-vasculaires, notamment l'hypertension artérielle, et lutter contre le diabète notamment en limitant la plage horaire où l'on ingère de la nourriture, conserver des contact sociaux notamment parce que celà oblige à faire attention à soit-même, combattre le tabagisme et dormir convenablement.

Cela est plus facile à écrire qu'à mettre en oeuvre.

2023 was marked by two events that I find regrettable: The marketing authorization of a drug (lecanemab) after an almost unsuccessful phase III clinical trial and dangerous side effects, and the proposal to redefine the disease of Alzheimer's disease based on molecules that are probably not biomarkers of this disease to facilitate obtaining marketing authorization.

Fortunately, there are more disinterested researchers, who are working on other hypotheses on the causes of Alzheimer's disease than those of amyloid plaques. The text discussed here, by Jennifer Erichsen and Suzanne Craft particularly highlights the link between insulin sensitivity, metabolic dysregulation, and inflammatory processes in the context of Alzheimer's disease.

It is well known that people with diabetes are at greater risk (1.6 times) of decline in cognitive function. The prevalence of moderate cognitive impairment in patients with diabetes is high (45%). This is presumably because, unlike most organs, brain functions require a constant supply of glucose as an energy source, so the brain is more sensitive to abnormalities in glucose metabolism.

The role of insulin is to trigger an intracellular signal that regulates the entry of glucose into our cells. Insulin resistance is one of the characteristics of diabetes but also of neurodegenerative diseases, as well as aging. It de facto leads to a sort of brain starvation.

There is a clear link between insulin and amyloid plaques: insulin is also involved in the clearance of beta-amyloid, a protein that forms the plaques characteristic of Alzheimer's disease. The authors believe that an impaired blood-brain barrier allows immune cells from the body to pass through, which leads to the activation of microglia in the central nervous system. Scientists point out that immune processes intensively consume energy, therefore glucose, and therefore insulin resistance slows down immune processes.

The progression of insoluble tau to neurofibrillary tangle pathology correlates with the progression of Alzheimer's disease symptoms. Insulin metabolism has been closely linked to tau protein. Pathological accumulation of tau leads to brain insulin resistance.

The main suggestion of the authors is to combine therapeutic interventions of different natures and to minimize side effects. This is certainly an important reflection which nevertheless does not seem to be common.

They cite for example that insulin delivery with specialized devices can quickly and directly transport insulin to the central nervous system, bypassing the peripheral nervous system to avoid hypoglycemia and other adverse systemic effects. A phase II clinical trial has shown some effectiveness with a specific device.

They also cite SGLT2 inhibitors, a class of drugs commonly used in diabetes, which reduce the risk of dementia by 42% in people with type 2 diabetes.

In conclusion, researchers believe that the elimination of amyloid is insufficient to stop, much less reverse the course of Alzheimer's disease and that significant risks accompany it.

They therefore propose researching adjuvants to improve efficacy and safety. They hope this next promising and essential step in the therapeutic pathway for Alzheimer's disease will begin quickly. ​

It's been known for more than 20 years that neprilysin inhibitors such as sacubitril could foster Alzheimer's disease. Yet in 2015, Novartis decided to ask the FDA to authorize Entresto (sacubitril/valsartan) for heart failure. A clinical trial was set up and failed to meet the primary objective (heart failure), nevertheless (usual story) the drug was authorized by FDA.

At that time it was well known that this drug could foster Alzheimer's disease, so the FDA mandated that another clinical trial was also designed (PERSPECTIVE; NCT02884206) to test if there was a risk to cognitive functions. There were also other clinical trials with the same goal, for example in Korea. These clinical trials didn't show any aggravation of cognitive functions.

More recent studies have suggested that this class of drugs (neprilysin inhibitors) could have both positive and negative effects on the development of Alzheimer's disease. . (source: Naif H. Ali and Hayder M. Al-Kuraishy)

A re-analysis of the results of another clinical trial by scientists from the University of Gothenburg, in collaboration with colleagues from the University of Glasgow, is less optimistic about the effects of sacubitril on cognitive functions.

There are many other drugs to manage heart failure and it is not even clear if Entresto brings substantial benefits to the patients. Why was Entresto authorized in the first place in 2015, and why is it still prescribed given the abundant literature about the effects of sacubitril on Alzheimer's disease?

Un article important est publié par Poul F Høilund-Carlsen et des collègues à travers le monde, sur la révision annoncée des critères de diagnostic de la maladie d’Alzheimer. Nos précédentes publications sur ce site, avertissaient déjà que cette révision aurait pour conséquence principale que les essais cliniques de médicaments seraient majoritairement approuvés, alors que la totalité des essais cliniques (324 de phase III) sur la maladie d’Alzheimer (y compris les médicaments récemment autorisés) se sont soldés par des échecs, et parfois par des effets secondaires dramatiques (ARIA).

Aussi bizarre que cela puisse paraître, les critères diagnostiques de la maladie d’Alzheimer ont subi de nombreux changements depuis 40 ans.

Initialement, elles reposaient principalement sur une évaluation clinique (l’état du malade). En 2011, l'Institut national américain sur le vieillissement et l'Association Alzheimer (NIA-AA) a approuvé, à des fins de recherche, un diagnostic de maladie d’Alzheimer préclinique basé sur l’imagerie médicale quand elle montre la présence de plaques d’amyloïde dans le liquide céphalo-rachidien. Pourtant on a démontré via des cohortes qu’un tiers des personnes âgées de plus de 75 ans peuvent avoir des plaques (et autres assemblages moléculaires) d’amyloïdes sans avoir de perte cognitive.

Cette proposition de diagnostic de 2011 ne concerne pas les médecins, elle est uniquement destinée aux scientifiques. On peut y voir une nouvelle illustration du principe que les outils distordent la perception du monde. En l’occurrence tester un malade avec un PET-amyloïde nécessite un quart d’heure et la présence d’une zone réagissant à un biomarqueur ainsi que d’une atrophie cervicale à l’imagerie, alors que tester la cognition est compliqué (y compris quand le patient ne veut pas coopérer) et toujours discutable par les proches.

En 2018, une série d'auteurs ont créé un nouveau cadre de recherche NIA-AA mettait un accent crucial sur « A », les biomarqueurs des plaques amyloïde-bêta (Aβ), et « T », les biomarqueurs de la protéine tau. En revanche, les biomarqueurs de la neurodégénérescence « (N) », notamment l’hypométabolisme et l’atrophie étaient indiqués entre parenthèses, indiquant un rôle diagnostique moindre.

La dernière révision (2023) proposée est non seulement dépourvue d’évaluation clinique, mais elle repose uniquement sur des molécules biomarqueurs, dont les rôles pathogènes n’ont jamais été prouvés. Ce qui est très grave c’est que les proposants souhaitent l'approuver non seulement pour la recherche mais également pour la pratique clinique et surtout pour les essais cliniques.

Les auteurs de cet article illustrent un résultat hypothétique de ce scénario: Celui ou un nouveau médicament serait efficace sans pour autant affecter la présence d’amyloïde et de tau dans le cerveau.

Ce médicament hypothétique, bien qu’améliorant l’état des malades, serait considéré comme un « échec » dans les essais cliniques. Pire les personnes qui présentent une amylose cérébrale et aucune démence seraient également identifiées comme des patients atteints de maladie d’Alzheimer.

Ce que les auteurs ne disent pas, ce qui est indicible dans notre société, c’est que les sociétés pharmaceutiques seraient les grandes gagnantes de ce changement. En effet la plupart des médicaments proposés depuis 5 ans sont efficaces contre les plaques amyloïdes, pour autant aucun n’est capable de montrer une amélioration de l’état de santé des malades.

Poul F Høilund-Carlsen et ses collègues proposent une procédure de diagnostic basée sur une évaluation clinique et des preuves in vivo d'une neurodégénérescence accrue qui est essentiellement la façon actuelle de diagnostiquer la maladie d’Alzheimer par les médecins.

Peut-être que les scientifiques devraient davantage fréquenter les Epahd, la maladie d’Alzheimer est quelque chose de beaucoup plus complexe que ce qu’ils pensent et enseignent.

On pourrait penser que le vieillissement affecte surtout les souvenirs anciens, c’est le contraire qui semble se passer. Pourquoi l’existence d’un conjoint ou d’un enfant est-elle occultée ?

On pourrait aussi penser que le trouble, une fois installé serait persistant. Pourquoi un malade se pense-t-il, se vit-il à une période de son enfance pendant quelques minutes puis sans trouble apparent est capable de se situer dans le temps présent?

On sait bien aussi que beaucoup de malades d’Alzheimer ont des troubles moteurs de type Parkinsonien (freeze). Il ne s’agit sûrement pas seulement d’un problème de mémoire ou de perte de cognition.

Mais le monde de la recherche médicale est, depuis la financiarisation de cette activité dans les années 80, gangrené par l’avidité mercantile. Il lui faut de l’argent rapidement et facilement, on est loin d'un idéal académique.

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.

Semantic wandering

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.

Conclusion

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.