Currently, there are few modifying treatments for Alzheimer's disease, approved drugs such as Aducanumab, Donanemab, and other antibodies target protein plaques and appear to have limited benefits at the cost of significant side effects. The European Interdisciplinary Council on Aging hosted a 2-day virtual meeting on November 24-25, 2022, to review the state of knowledge on the link between infection and neurological disorders, and dementia. We describe in this post an article which is itself the summary of the proceedings of this meeting. Our intention is educational, and the thesis is interesting but the article is often confusing. This is not a straightforward summary, we modified many statements into conditional mode.

The thesis of the article is that of an infectious etiology for dementia and in particular Alzheimer's disease. Infiltration of the brain by pathogens could act as a trigger or a cofactor of Alzheimer's disease. This thesis has been postulated several times over the past 30 years. This was also described about Parkinson's disease by Heiko Braak in 2003.

The first efforts to identify a causal link between neurodegenerative disorders and infection began in the early 1980s, but already Alois Alzheimer and very shortly after, Oskar Fischer evoked the possibility of an infectious origin for this type of dementia.

The microbial hypothesis of Alzheimer's disease postulates that the physiological disturbances associated with aging allow the infection of a healthy brain by viruses, bacteria, or other pathogenic agents (fungi, parasites). These pathogens would lead to increased production of amyloid-β (Aβ) and the aggregation of hyperphosphorylated tau protein, which would lead to neurodegeneration.

Following infection, these viruses can enter a latent phase and potentially reactivate decades later if the immune system weakens.

Genes, neuroinflammation, and dementia

The term “dementia” refers to a complex syndrome that results from a lifetime interaction of genetic, lifestyle, environmental, and age-related factors. Alzheimer's disease is the most common cause of dementia, but several other diseases can also cause dementia.

Heritability shows great variability in the different forms of dementia, ranging from 5-50%, with some having a very low degree of heritability, while others, such as frontotemporal dementia (FTD), have high heritability.

In addition, chronic low-grade inflammatory mechanisms have been implicated in a variety of neurodegenerative conditions including Alzheimer's disease.

A poorly studied aspect of neuroinflammation is the gender effect. Autoimmune diseases are more common in females (which account for up to 80% of cases), and females generally have increased immunoreactivity compared to males.

In most cases of physiological apoptotic cell death, efferocytosis prevents inflammation and other pathological conditions. However, when apoptotic cells are not effectively eliminated, destruction of apoptotic cell membrane integrity, leakage of intracellular contents, and secondary necrosis may ensue.

However, clinical trials that have investigated compounds with anti-inflammatory properties to modulate neuro-inflammatory processes in dementia have been unsuccessful.

The Antimicrobial Hypothesis of Alzheimer's Disease

Alzheimer's disease was first recognized based on the accumulation of neurofibrillary tangles and beta-amyloid protein deposits in the brain, and these features became the pathological hallmarks of dementia. This gave rise to what is commonly known as the amyloid cascade hypothesis of Alzheimer's disease, and at the heart of this theory is the beta-amyloid protein, which has receptors on many cell types. and can stimulate receptors to enter cells signaling pro-inflammatory transcription, moving toward microglia activation and neuron destruction. This theory focused primarily on the beta-amyloid protein as the primary culprit in Alzheimer's disease. However, as noted above, it has become apparent in recent years that neuroinflammation is also a very important contributing factor, with growing knowledge of an association between the immune system and Alzheimer's disease.

However, a key issue that has undermined the validity of this paradigm is the failure of many clinical trials targeting beta-amyloid protein. Although drugs targeting amyloid can reduce amyloid protein load, there has been no clinically significant effect on the disease. Even if several antibodies have recently been approved by regulatory authorities, this has been done in a very controversial way.

Moreover, new evidence suggests that beta-amyloid also has many biological roles, and these functions are neuroprotective at low levels but pathological at high levels. Other arguments that contradict the amyloid cascade hypothesis are that beta-amyloid is found in high concentrations in many older people who do not have dementia, while many demented patients do not have dementia. beta-amyloid.

There is a very early involvement of the innate immune system in Alzheimer's disease, which is a systemic disease with complex interactions between the periphery and the brain. The common pathway is neuroinflammation, and infection is a trigger that, over decades, will initiate and sustain pathways that ultimately result in the disease known as Alzheimer's disease, manifesting as cognitive decline. However, it might be better to no longer call this clinical manifestation Alzheimer's disease, but rather a chronic cerebral insufficiency, potentially of multiple origins, all leading to neurodegeneration.

Clinical relevance of the gut-brain axis in dementia

The intestinal microbiome is a community of microorganisms, mainly bacteria but also viruses and fungi, living in symbiosis with the host in the intestines, with increasing loads from the duodenum to the distal part of the colon. Modern sequencing techniques make it possible to measure the biodiversity and abundance of bacterial taxa within a fecal sample and assess the variability within a given population.

In healthy adults, the gut microbiota comprises about 10 phyla, with most species belonging to 2 phyla (Bacteroidetes and Firmicutes). Some taxa are strongly represented (e.g. Bacteroides, Prevotella, Alistipes, Eubacterium), while there are a large number of minor players poorly represented but with relevant metabolic activity, such as those that can produce chain fatty acids short (SCFA) (for example, Faecalibacterium, Butyrivibrio, Succinivibrio, Ruminococcus).

From childhood, the intestinal microbiota is shaped towards a state that is reached around the age of 10 years. In healthy adults, the intestinal microbiota is characterized by a certain resilience to transient disturbances. The large variability observed in adults depends on environmental factors, e.g. diet, location, drug use, exercise, and disease, all of which can shape the structure and composition of the gut microbiota and affect interindividual variability.

During aging, the gut microbiota faces significant compositional changes, including a reduction in biodiversity. In addition, the aging microbiota is less stable over time and less resistant to stress factors such as courses of antibiotic therapy.

It is therefore possible that the structure of the intestinal microbiota is involved in aging. The intestinal microbiota could therefore influence the pathophysiology of dementia. Indeed, it is known that the intestinal microbiota can establish a connection with several organs outside the gastrointestinal system, in particular, the brain via the vagal nerve.

• The vagus nerve regulates gastrointestinal function and motility and, indirectly, the composition of the gut microbiota. The vagus nerve in the intestinal mucosa also has afferent vagal endings that express receptors sensing microbial metabolites and toxins.

• Dysbiosis of the intestinal microbiota leads to the production of cytokines and the activation of intestinal immune cells.

• Dysbiosis of the intestinal microbiota induces alterations in the permeability of the intestinal mucosa, allowing the entry into the systemic circulation of not only bacterial toxins like LPS, but also living microbes themselves, which can activate immune cells in circulation, promoting a systemic inflammatory response, which can affect microglia, leading to microglial activation and beta-amyloid deposition. Indeed, studies in mouse models have highlighted a complex interplay between the leaky gut and the leaky blood-brain barrier, particularly at the choroid plexus. In an animal model, closure of the choroid plexus barrier has been shown to be associated with mental deficits.

Many bacteria in the gut microbiota can produce short-chain fatty acids (SCFAs), which are important physiological mediators for the host. SCFAs can improve insulin sensitivity, stimulate adipose tissue catabolism, and modulate inflammation in the host. However, despite these primarily protective functions, once dementia is established, SCFAs may contribute to increasing rather than inhibiting amyloid deposition.

A Japanese study by Ueda et al. shown that depletion of the SCFA producer Faecalibacterium prausnitzii was a hallmark important for people with Alzheimer's disease. The authors isolated the strains markedly depleted in people with Alzheimer's disease and MCI compared to healthy subjects, and administered these strains as oral probiotics to Alzheimer's disease model mice, and showed that it resulted in improved cognitive testing!

Specific pathogens and neurological disorders * Complications related to SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters lung cells via spike proteins, which confer the ability to enter cells via the ACE2 receptor, allowing virus activation and migration into the system. The virus can then spread to other organs. SARS-CoV-2 promotes the aggregation of misfolded proteins in neurons and the brain through various direct and indirect actions. mechanisms, leading to neurodegeneration and cognitive dysfunction. The impact of the virus on lung function and hypoxia promotes neurodegeneration and cognitive decline.

• HIV-associated neurocognitive disorders Neurocognitive disorders seen in HIV carriers are called HIV-associated neurocognitive disorders (HAND). The diagnosis is made mainly by exclusion. HIV reaches the cerebrospinal fluid and the brain as early as the sixth day after infection. It should be noted, however, that HIV cannot affect neurons, as neurons lack CD4 and CCR5 receptors, but it can infect microglia, astrocytes (at least partially), and oligodendrocytes. This generates long-term low-grade inflammation, producing neurotoxic products which then can damage neurons because the role of the cell types that make up glia is to support neurons.

A challenge in HIV drug therapy is to achieve a balance between neurological efficacy and neurotoxicity.

Herpes simplex virus type 1 (HSV-1)

After primary infection, herpes viruses can remain latent in the body and can be reactivated later by stress, immunosuppression, or inflammation. Reactivation of the virus, referred to as productive infection, causes direct viral damage and inflammation, and recurrent events over time likely cause cumulative damage. With the advent of polymerase chain reaction (PCR) techniques in the 1980s, the first demonstration that HSV-1 DNA could be detected in the brains of patients with Alzheimer's disease was provided.

It is now established that the association of HSV1 DNA in the brain and the type 4 allele of the apolipoprotein E gene (APOEe4, a known susceptibility factor for Alzheimer's disease) confers a high risk of Alzheimer's disease. HSV-1 infection produces abnormally phosphorylated beta-amyloid and tau protein.

Flu and dementia Another pathogen that has been shown to be able to enter the CNS is the influenza virus. Influenza is sometimes associated with neuropsychiatric disorders, including confusion, delirium, seizures, and encephalopathy. However, the literature on the risk of dementia after influenza is generally negative.

Influenza vaccination was, however, associated with a reduced risk of Alzheimer's disease, suggesting that influenza vaccination could be a simple and inexpensive intervention to prevent dementia.

Conclusion

Over the past few decades, remarkable progress has been made in our understanding of the role of microorganisms in neuroinflammation and dementia. However, the encouraging preclinical results have not translated into such compelling results in human clinical studies. A major problem is that clinical trials last a few months when it can take years, even decades, between primary infection and the subsequent onset of cognitive decline. A particularly attractive preventive option is the wider use of vaccines to prevent infection, thereby mitigating the possible harmful effects of infection on the brain, with the potential for cognitive decline.

Chronic stress is a major risk factor for depression and can also disrupt the gut microbiome. For example, certain intestinal bacterial strains have the ability to induce anxious behaviors. Truncal vagotomy is associated with a decreased risk of later Parkinson's disease, but the effect of vagotomy on dementia is unclear.

Scientists from France wanted to test the hypothesis that the vagus nerve, a key two-way communication pathway between the gut and the brain, might mediate the effects of stress-induced gut microbiome changes on hippocampal plasticity and behavior.

For this, they used fecal samples from mice that underwent unpredictable chronic mild stress to inoculate healthy mice and assess the effects of gut microbiome changes on brain function and behavior. To be able to test how the vagal nerve can influence brain function, they performed a subdiaphragmatic vagotomy on these mice before performing the gut microbiome transfer. Mice underwent vagotomy 2 weeks prior to inoculation with gut microbiota from control mice. Fecal samples were collected 7 weeks after inoculation.

The mice thus treated adopted the behavioral phenotype of donor-stressed mice, which is characterized by depression-like responses. these results indicate that the inoculation in healthy mice of a disturbed gut microbiota results in neuronal activation, associated with a decrease in the expression of key enzymes involved in the biosynthesis of serotonin and dopamine, and a decrease in neurogenic factors which quickly has an impact on neuronal generation.

To assess whether the vagus nerve transduces these changes in the gut microbiota that are induced by stress, the scientists used additional cohorts of animals that underwent subdiaphragmatic vagotomy or sham surgery 2 weeks before fecal transplantation.

The mice were anesthetized and their stomach and lower esophagus were gently exposed after a mid-lateral incision of the skin and abdominal wall, and the intestine was retracted to allow access to the stomach. A ligature was placed around the esophagus as it enters the stomach to allow gentle retraction and clearly expose both vagal trunks. These were dissected and all of the neural and connective tissue surrounding the esophagus below the diaphragm was removed to transect all small vagal branches. A 2 week recovery period was allowed before the behavioral experiments took place.

They found that vagus nerve ablation suppressed gut microbiota-mediated transmission of depressive-like states. Specifically, unlike sham-operated mice, vagotomized mice did not exhibit a decrease in preference for sucrose (fructose). In addition, inoculation of gut microbiota in animals that had undergone surgery but not ablation significantly increased latency to eat and their immobility, whereas these depressive-like responses were absent in vagotomized animals.

In addition, vagotomization of mice protected against the decrease in cell proliferation and neuronal differentiation induced by inoculation with gut microbiota harvested by UCMS. These results indicate that vagus nerve integrity is necessary for the transmission of the depression-like phenotype and deficits in adult HPC neurogenesis after inoculation with a disrupted gut microbiota.

Thus, inoculation of healthy mice with gut microbiome derived from unpredictable chronic mild stress mice, would well activate the vagus nerve and induce early and sustained changes in serotonin and dopamine neurotransmission pathways in the brainstem and seahorse.

It is well known that the vagus nerve acts as a conduit carrying signals from the gut to the brain and vice versa. The present study demonstrates that chronic stress-induced gut microbiome disruptions induce rapid deficits in serotonin and dopamine neurotransmission in the brainstem and hippocampus, early and late neuroinflammation, and alterations in adult hippocampal neurogenesis. which are ultimately associated with depressive states. The mediator of these alterations would be the vagal nerve which would act as an intermediary between the intestine organ and the brain.

This suggests that vagal afferents are potential targets for therapeutic intervention for stress-related disorders, including depression.

The brainstem and the hippocampus are two structures buried deep inside the skull. The hippocampus is one of the first structures affected in Alzheimer's disease, which explains the memory problems and disorientation that characterize the appearance of this neurodegenerative pathology. Hypoxia (oxygen deprivation), encephalitis, and temporal lobe epilepsies are also conditions presenting damage to the hippocampus. People with severe damage to the hippocampus are susceptible to different types of amnesia.

It is in the brainstem that the substantia nigra is found, which is implicated in Parkinson's disease. This area is involved in particular in motor skills, and in particular in the control of posture. But it also participates in non-motor functions (cognition, emotions, etc.). It has been associated with several diseases:

• Parkinson's disease;
• Gilles de la Tourette's disease;
• Huntington's disease;
• Wilson's disease;
• myoclonic dystonia.
• In addition, it would play a role in psychoses, such as schizophrenia

The scientists, therefore, concluded that subdiaphragmatic vagotomy abrogates adult hippocampal neurogenesis deficits, neuroinflammation, and depression-like behavior, suggesting that vagal afferent pathways are required to drive gut microbiome-mediated effects on the brain.

These results are consistent with previous findings showing that the vagus nerve mediates the effects of certain probiotic strains on stress responses in rodents and on neurotransmission and neuroplasticity. However, this study does not identify specific bacterial strains that could impact the brain via a vagus-hippocampal nerve circuit.

On the other hand, the use of subdiaphragmatic vagotomy as a means of abolishing vagus nerve activity is a quick and inexpensive but not necessarily conclusive procedure. Indeed, if the vagus nerve has a profound influence on the health of the brain, removing it makes it difficult to interpret the results.

Finally, it should be emphasized that not all microbial signals to the brain are mediated by the vagus nerve. For example, anxiety-like behavior in mice induced by mild gastrointestinal infection is still evident after vagotomy, indicating that other biological pathways (some of which are known to be influenced by the microbiota) may mediate the anxiogenic effects of the intestine. microbiota, such as microbial metabolites or by-products and immune mechanisms.

Manipulating the gut microbiome-vagus nerve-brain pathway by activating the vagus nerve or altering the gut microbiota would therefore be an opportunity in the quest to develop alternative therapies for treatment-resistant depression. Dosage trials of vagus nerve stimulation are ongoing in treatment-resistant depression, and the results of these studies in conjunction with clinicians' cumulative experience will determine future treatment choices.

In addition to representing a new therapeutic modality, vagus nerve stimulation therapy is a research tool that offers hope for a better understanding of the mechanisms underlying depression.

Les théories qui affirment que le vieillissement n’est pas programmé dans notre organisme, ne fournissent pas de réponse convaincante à différentes observations. Par exemple comment se fait-il que la durée de vie soit relativement constante au sein d’une espèce donnée et que différentes espèces puissent avoir une différence de jusqu’à 1000 fois dans leur durée de vie? La seule possibilité c’est que cette « horloge » soit codée dans le génome. Des chercheurs Ecossais argumentent dans une nouvelle publication qu’il y a une horloge biologique, qu’elle est logée dans le cerveau, qu’elle influence grandement le système immunitaire. Ils illustrent cela avec la cas de la maladie d’Alzheimer.

Cette horloge, qu’ils nomment horloge circavitale, orchestrerait les changements liés à l’age via le renouvellement des cellules souches des systèmes physiologiques du corps.

La perte de cheveux, les effets indésirables gastro-intestinaux et rénaux sont couramment rencontrés chez les patients recevant une chimiothérapie qui inhibe la production de nouvelles cellules souches, et des troubles cognitifs transitoires sont également signalés.

A contrario, lles expériences de parabiose montrent que le vieillissement peut être manipulé via la circulation sanguine.

Cela pourrait impliquer que de façon similaire aux horloges biologiques circadiennes et circannuelles, il existerait une « horloge maîtresse de l'âge » (horloge circavitale) qui serait située dans le cerveau limbique des mammifères. Cette horloge modulerait les changements systémiques du facteur de croissance et de la sécrétion hormonale au cours de la vie, ainsi que les altérations systémiques. dans l'expression génique telle que la méthylation génomique.

L'ablation chirurgicale de l'hypothalamus chez les hamsters est associée à une durée de vie réduite, et son maintien en ordre de marche à l'aide de tissu hypothalamique fœtal augmente la durée de vie de plus de 4 mois, ceci est remarquable pour une espèce dont la durée de vie est comprise entre 11 et 18 mois. Les lésions cérébrales sont une cause connue d'immunodéficience.

Les études sur le vieillissement accéléré chez la souris, ainsi que sur les gènes de longévité humaine, convergent vers les facteurs de croissance des fibroblastes (FGF) conservés au cours de l'évolution et leurs récepteurs, y compris KLOTHO, ainsi que les facteurs de croissance analogues à l'insuline (IGF) et les hormones stéroïdes, en tant qu'acteurs clés de la médiation les effets systémiques du vieillissement.

Les cellules fibroblaste ont plusieurs rôles dans l'organisme, dont :

• un rôle protecteur contre la constitution d'athéromes, via la métabolisation du cholestérol ; • le renouvellement du collagène et des protéines des fibres grâce à leur fabrication et aussi leur destruction assurées par des métalloprotéases (collagénases et protéases) ; • la défense anti-infectieuse et antivirale par la sécrétion de facteurs chimiotactiques (MCP, MIP) et d'interféron β.

La protéine Klotho, elle, a un rôle important dans la lutte contre le processus de vieillissement. Une étude a montré qu'un défaut d'expression du gène chez la souris entraînait un syndrome ressemblant au vieillissement humain : durée de vie réduite, infertilité, artériosclérose, atrophie cutanée, ostéoporose et emphysème. Une étude publiée en 2005 a trouvé que la surexpression de Klotho était à l'inverse associée à une augmentation de leur durée de vie.

On suppose que les changements liés à l'âge de ces facteurs et de plusieurs autres facteurs entraînent un déclin progressif de l'entretien des tissus biologiques en raison de l'échec de la reconstitution des cellules souches.

Cela affecterait plus particulièrement le système immunitaire, qui nécessite un renouvellement constant des cellules souches de la moelle osseuse. Le déclin immunitaire lié à l'âge augmenterait donc le risque d'infection alors que la durée de vie peut être prolongée chez les animaux dans des environnements sans germes.

Cet élément et d'autres suggèrent que l'infection est la principale cause de décès chez les organismes supérieurs. Le déclin immunitaire est également associé aux maladies liées à l'âge. C’est la thèse de Richard Lathe et David St Clair , qui argumentent que la maladie d'Alzheimer est causée par l'immunosénescence et l'infection.

En effet, la protéine signature du cerveau la maladie d'Alzheimer, Aβ, est maintenant connue pour être un peptide antimicrobien, et les dépôts d'Aβ dans le cerveau la maladie d'Alzheimer peuvent être une réponse à une infection plutôt qu'une cause de maladie.

L'idée que la la maladie d'Alzheimer pourrait être associée à une infection a une longue histoire. Fischer a ainsi écrit "J'ai souligné la similitude particulière des Drusen {dépôts amyloïdes} avec les colonies bactériennes". Néanmoins, pendant longtemps, les spécialistes de la maladie d'Alzheimer ont été d'avis que les dépôts d'Aβ observés dans le cerveau des patients atteints de la maladie d'Alzheimer étaient la cause de cette maladie.

Pourtant des éléments solides indiquent que le peptide Aβ doit être l'une des composantes du système immunitaire inné. Ce peptide possède en effet une activité d'inactivation robuste contre différentes bactéries, levures et virus.

Ce pourrait-il que le cerveau (comme tous les autres tissus examinés) abrite son propre microbiome, et que celui-ci augmenterait avec l'âge ? C’est assez probable. Dans ce cas, ces infections à répétion au cours de la vie pourraient influencer cette horloge circavitale, et petit à petit la dérégler.

Étant donné que certaines personnes âgées cognitivement normales présentent une neuropathologie étendue, les auteurs affirment que la localisation précise de la pathologie dans le cerveau - en particulier, les lésions du cerveau limbique où se trouverait cette horloge circavitale - détermine le degré d'immunosénescence et pourraient donc sous-tendre un cercle vicieux de déclin immunitaire accéléré et de prolifération microbienne qui culmine dans la maladie d'Alzheimer.

Ce modèle général pourrait être étendu à d'autres maladies liées à l'âge, et ils proposent un paradigme général de la sénescence de l'organisme dans lequel le déclin de la prolifération des cellules souches entraîne une immunosénescence et une mortalité programmées.

Mais il ne s'agit que d'une théorie parmi de multiples autres.

Passiflora (passion fruit), which is widely employed in folk medicine as well as in the pharmaceutical industry, shows benefits for anxiety, nervousness, constipation, dyspepsia, and insomnia. This may stem from the fact that it is sometimes used to make a tea used as a sedative.

Yet the herbal pharmacopeia is highly heterogeneous. Passiflora genus, Passifloraceae, includes about 520 species. It's even not clear if the supposed benefits come from the plant or from endophytes (fungi or bacterium).

It is known that amphiphilic stilbene derivatives attenuate the neurotoxicity of soluble Aβ42 oligomers by controlling their interactions with cell membranes. Stilbene derivatives include resveratrol. Endophytic fungi isolated from various types of grapevines and Polygonum cuspidatum, the primary plant sources of resveratrol, demonstrated intriguing resveratrol-producing ability.

Only a handful of studies have been made on Passiflora edulis and Alzheimer's disease. Scientists from Vietnam and Algeria evaluated for neuroprotective activity in murine Alzheimer's disease model induced by aluminum chloride and D-galactose.

While those are not common animal models of Alzheimer's disease, they have a good reputation as good models of this disease to the point that some scientists still suggest that the dismissed relation between aluminum and Alzheimer's disease may have some substance after all.

The scientists analyzed the phytochemical properties of the polyphenolic stilbene-rich acetone fraction and showed that it contained different stilbenes including trans-piceatannol, scirpusins A-B and cassigarol E. Piceatannol is a metabolite of resveratrol.

The total phenolic content (TPC) of Passiflora edulis was 413.87 mg eqv/g which is much less than green tea.

When the Alzheimer's mice were treated at 100 mg/kg and 200 mg/kg, they spent less than 47% and 66% of the time in a Morris maze, respectively, than non-treated Azheimer's model mice.

Two simple stilbenes, trans-piceatannol and trans-resveratrol, showed selectively inhibitory activity in silico against AChE.

Two stilbene dimers, cassigarol E and scirpusin A, exhibited low inhibitory potential against AChE and BChE, significantly lower than those of the positive control, donepezil, and tacrine.

These findings suggest that the stilbenes from P. edulis seeds, particularly the stilbene dimers, warrant further investigation as potential neuroprotective candidates in the prevention of cognitive deficits associated with Alzheimer's disease.

Biomedical research has revealed many similarities between neurodegenerative diseases at the cellular level, including atypical protein assemblies. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well. In each disease, neurons gradually lose function as the disease progresses with age. It is though that repeated viral exposures, even seemingly innocuous, can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.

Yet the search for a specific viral or auto-immune origin in these diseases have mostly failed. This article published on medRxiv by scientists from Netherlands, aims at identifying overlap at genetic level between four investigated neurodegenerative disorders (Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease).

As these diseases are mostly associated with age, they have a poor heritability, so it would be difficult to associate with some gene.

As in previous studies, the authors failed to identify any region, gene, gene-set, cell or tissue type that was shared between all four neurodegenerative diseases. However, they found that HLA locus was significantly associated with these traits. It is not clear how it is associated because the scientists used a tool named FUMA. FUMA is an automatic tool which annotates GWAS findings and prioritizes the most likely causal SNPs and genes. Yet it is a bit obscure like all these "ontological" tools, like too often in molecular biology it is a qualitative, not quantitative tool.

HLA is a part of the genome which plays an important role in immune systems. The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. This genetic complex is called HLA in humans.

These cell surface proteins are called MHC molecules. The proteins encoded by HLAs are those on the outer part of body cells that are (in effect) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.

While this study does not try to explain what is the relation between those diseases and the HLA region, it is possible to make some guesses.

If aging (and DNA) degradation is a function of the number of viral attacks during life, then it makes sense to find a correlation between immune system and these non-communicable diseases.

But again many studies have not found any relations between viral or auto-immune insults and neurodegenarative diseases.

Des scientifiques de l'université de Virginie ont découvert que l'exposition aux inhibiteurs nucléosidiques de la transcriptase inverse était associée à une incidence significativement plus faible de la maladie d'Alzheimer dans deux des plus grandes bases de données d'assurance maladie aux États-Unis.

La signalisation immunitaire innée via l'inflammasome NLRP3 semble être impliquée dans la pathogenèse de la maladie d'Alzheimer, du diabète ou de la dégénérescence maculaire. NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome, it  detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

Dans la présente étude, les scientifiques démontrent que l'exposition aux NRTI inhibiteurs de l'inflammasome est associée à une incidence significativement plus faible de la maladie d'Alzheimer dans deux des plus grandes bases de données d'assurance maladie aux États-Unis. Une thérapie qui inhibe l'activation de l'inflammasome pourrait donc peut-être être neuroprotectrice dans la maladie d'Alzheimer.

Cependant, les toxicités associées à l'utilisation systémique des NRTI, réduisent l'enthousiasme pour de telles entreprises thérapeutiques. Fait intéressant, la fonction anti-inflammatoire des NRTI est indépendante de leur capacité à inhiber la transcriptase inverse. Les dérivés alkylés de NRTI modifiés connus sous le nom de Kamuvudines, conservent la capacité d'inhiber l'activation de l'inflammasome mais n'ont pas la capacité d'inhiber la transcriptase inverse et, par conséquent, n'ont pas non plus les toxicités associées aux NRTI classiques.

Tout au long des analyses de bases de données d'assurance maladie, des mesures ont été prises pour atténuer les biais potentiels et promouvoir la validité interne. Au départ, les scientifiques ont ajusté un grand nombre de variables démographiques et cliniques en les incluant comme covariables de facteurs de risque fixes. Dans l'ensemble, ces mesures appuient la validité et les conclusions des analyses de bases de données.

Bien que les échantillons de la base de données aient été limités aux patients atteints du VIH ou de l'hépatite B, il est tentant de supposer que les résultats de l'étude peuvent être généralisés à d'autres populations de patients.

Ainsi, les effets neuroprotecteurs des NRTI et de la Kamuvudine-9 dans la maladie d'Alzheimer s'étendent probablement au-delà du cadre d'une infection virale coexistante.

Ceci est cohérent avec des études antérieures par nous et d'autres qui démontrent les avantages anti-inflammatoires des NRTI et de la Kamuvudine-9 dans d'autres modèles de maladies non infectieuses.

Les auteurs présentent également des éléments indiquant que le traitement par Kamuvudine-9 de souris âgées 5xFAD (un modèle génétique de la maladie d'Alzheimer) inverse considérablement les déficits de mémoire spatiale et d'apprentissage et améliore leurs performances par rapport à celles des jeunes souris non modifiées génétiquement.

Néanmoins, des essais contrôlés randomisés prospectifs chez l'homme sont justifiés pour mieux comprendre les effets des NRTI ou de la Kamuvudine-9 sur les résultats cliniques dans la maladie d'Alzheimer. En effet, des essais sont en cours sur deux NRTI, la lamivudine (NCT04552795) et l'emtricitabine (NCT04500847), dans la maladie d'Alzheimer. Il convient de noter que l'utilisation isolée d'inhibiteurs nucléosidiques de la transcriptase inverse peut faciliter le développement d'une résistance virale. De plus, les NRTI ont été associés à une toxicité mitochondriale hors cible en raison de leur inhibition de la gamma polymérase mitochondriale23. Il convient donc de tester si Kamuvudine-9, qui ne présente pas ces inconvénients, pourrait être une alternative plus sûre aux NRTI en milieu clinique.

Il convient de noter qu'Inflammasome Therapeutics, une société privée de Newton, Massachusetts est fondée par Ambati et Paul Ashton.

Studies in health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions have shown that low-dose irradiation (10 cGy) causes down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease. Curiously Mice exposed to high-dose radiation (2 Gy)did not show these effects and associations. Intriguily, there are also reports indicating stimulatory or beneficial effects after exposure to cell phone radiofrequency radiation.

Increased brain glucose consumption after exposure to radiofrequency radiation, as confirmed by PET studies, may be a potential mechanism in this phenomenon. Some scientists think that this is related to the possible beneficial effects of infrared exposure that are sometimes asserted.

Moreover, Schuz et al. in 2009 reported that long-term cell phone users had a 30–40% decreased risk of hospitalization due to AD and vascular dementia!

Following similar observations, Beaumont Cancer Center in Michigan USA, began treated patients Alzheimer's disease with ionizing radiation at doses of 30 to 60 Gray (Gy) given in 2 Gy fractions.

In 2015 in Canada, a patient in hospice with Alzheimer's disease was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home.

This was described in a report which was criticized for failing to acknowledge alternate hypotheses and confounding variables.

Two clinical trials were conducted in Canada with 5 patients in one case and 4 patients in the other, but no results were posted which presumably was due to an absence of positive results. Yet minor improvements on quantitative measures were noted. It should be noted that for having statistical significance a clinical trial should enroll several hundreds to thousands patients. Otherwise it's easy to make unsubstantiated claims.

A clinical trial with 5 patients was interrupted by COVID-19.

It seems history is repeated, a new publication describes another clinical trial with 5 patients, this time in USA at Barrow Neurological Institute.

Five patients were treated with LD-WBRT (a new acronym for radiotherapy) (2Gy x 5). Three subjects were female and two male. Four of the 5 patients experienced minimal improvement or stability in MMSE-2 scores comparing baseline before treatment and post-treatment scores at 12 months. The mini–mental state examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. Three patients saw their scores improve, another remained stable, and the last experienced a considerable drop in the MMSE score. Curiously the publication does not provide any clinical trial registration number.

Metabolism is the conversion of energy from food into energy for life-sustaining tasks such as breathing, circulating blood, building and repairing cells, digesting food, and eliminating waste. For sedentary adults, basal metabolic rate (the metabolic rate at rest) accounts for about 50% to 70% of total energy output, dietary thermogenesis for 10% to 15%, and physical activity for the remaining 20% to 30%.

At approximately 60 years old, BMR begin to decline, along with fat mass. However, declines in energy expenditure exceed that expected from reduced body mass alone. This is similar that what is found in several neurodegenerative diseases, albeit at a much slower rate.

Numerous studies suggest that metabolic dysfunction increases the risk of Alzheimer's disease. For instance, impaired glucose metabolism in the brain has been linked to Alzheimer's disease and may start several years before the onset of clinical symptoms.

Due to the long incubation period between exposure and results, randomized controlled trials, the gold standard for causal reasoning, are not feasible. In addition causation and confounding often substantially impede or mislead the interpretation of results from epidemiological studies. So scientists use Mendelian randomization, which is a method for obtaining unbiased estimates of the effects of a putative causal variable without conducting a traditional randomized controlled trial.

In a new publication, scientists determined the causal relationship between BMR and Alzheimer's disease by two-way Mendelian randomization and investigated the impact of factors associated with BMR on Alzheimer's disease.

The authors searched for a possible causal relationship between Alzheimer's disease and factors related with BMR, hyperthyroidism and type 2 diabetes, height and weight.

BMR was found to have a causal relationship with Alzheimer's disease, but there was no causal relationship between hyperthyroidism or type 2 diabetes in one hand and Alzheimer's disease in the other hand.

The authors' study showed that higher BMR reduced the risk of Alzheimer's disease, and patients with Alzheimer's disease had a lower BMR.

A person may be able to change their BMR through regular cardiovascular exercise.

Read the original article on Pubmed