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The Most Important Question in Alzheimer’s Investing
The question is a simple one. Is Alzheimer’s a disease or a syndrome?. If it is a disease then it shall have one particular etiology with one drug to it. Of course, this is a great exaggeration but serves its purpose of illustration the difference between a disease and a syndrome, which is a set of symptoms that can have varied etiology. Talking more in terms of game theory, investing in Alzheimer’s drugs can be zero sum game or game where many are going to be winners, although fractionally. This view has been already expressed by Dr. Missling. I have also previously raised the question of disease vs. syndrome.
In very simplistic way the Alzheimer’s disease can be explained as the onset of cognitive impairment, followed by the plaque deposits and finally appearance of the tau tangles, all with continued decline in cognitive abilities. That is at least the scenario followed by the murine models of AD. Humans have a bit different response, as 30% those who had been diagnosed with AD at death had no amyloid plaque deposits. In regards to dementia itself and AD, we can see “three diseases”. The early onset AD, let’s say at age of 50 years and up to 10 years of duration, leading to death. Second, gradual cognitive decline with age. The third, with advancing old age and already age related congnitive decline, diagnosis of AD and the usual precipitous cognitive deterioration, often cut short by death due to other morbidity. This is the extremely simplified view of the epidemiology of dementia and AD. For reference see post link: https://piotrpeterblog.com/2021/04/11/the-ideal-dementia-drug-and-dementia-patients-population/
Etiology is the fancy name given in medicine to the cause of a disease or a condition. There are hundreds if not thousands of papers written every year about dementia and AD. Some are just reviews of literature on some aspect of the disease, some bring genuine new knowledge. But none of them are the full and complete answer to the question what are the causes or a cause of AD. Let’s for the sake of an argument claim that AD as a disease depends upon 100 interactions. A researcher can not follow all of them in vitro or in a murine model. He will concentrate on one or perhaps few to get a partial view of the disease. It is the clinical part of the search for new drug to give the final verdict on the benefits of the drug. The more limited is the scope of the study the less ambiguous are the results of the study and the more convincing they are. the caveat here is that much can lost in effort to limit the scope in order to lessen ambiguity.
I have written about some of the studies on AD. The etiologies given by them range from genetics mutations, epigenetic changes in genes during the life time of patients (chromatin remodeling), mitochondrial health, oxidative stress, neurotransmitters, misfolded protein, and neurotropic signaling molecules. They all can be aspects of one disease. The latest, I read about the possible etiology of AD due to infection by P. gingivalis, the same bacterium causing periodontal disease. If you shop for one and only cause of the disease it seems to the right place. Scientists at $CRTX claim that it is so and give studies to support their view. Indeed, it is a compelling evidence. It would explain the amyloid plaque failure and appearance in later times of tau tangles.
From ALZHEIMER’S DISEASE-LIKE NEURODEGENERATION IN PORPHYROMONAS GINGIVALIS INFECTED NEURONS WITH PERSISTENT EXPRESSION OF ACTIVE GINGIPAINS. JOURNAL OF ALZHEIMER’S DISEASE 2020.
Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho- tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.
Bacterium P. gingivalis might colonize the brains of the infected persons and stay there dormat for decades as expresed by researchers in words “viable but not culturable”, meantime the bacterium produces proteases which are sources of its virulences. Collectively, they called gingipains. Proteases are enzymes which cut proteins and peptides into parts, functionally destroying them or even producing toxic residue. These can also be found in the CSF (celebrospinal fluid) of infected persons. The in-vitro models provided by $CRTX suggest that the amyloid plaque and tau tangles are direct results of the infection.
About 50% of population of The US after age of 30 years is infected with the bacterium. The picture that the scientists at Cortexyme paint is that of bacterium taking a ride on some cells of the immune systen through brain blood barrier, and slowly spreading from neuron to neuron. Virulence of P. gingivalis causes neuroinflammation leading to production of A-beta amyloid plaque as defence mechanism and later on dissolution of microtubules resulting in tau tagles. Here, we can talk about the disruption of axonal transport, and loss of synapses. Ultimately, neurons are driven to cellular death called pyroptosis. The definition of pyroptosis says that it is the type of programmed cell death taking place in the event the cell has been infected and cannot be rescued.
This is a picture of low level infection which can be dormant for 30-40 years, which correponds to the murine model of 22 weeks incubation period to symptoms of AD. The murine and in-vitro utilize very high ratio of bacterium to cell ratio which makes the infection highly probable. Under real conditions these can never be achieved in a living person. Nevertheless, some people can be susceptible to the infection, as well as can have high levels of neuroinflammation. The authors conceded this truth.
The number of people infected with P. gingivalis is vast. Only minority develops Alzheimer’s. Let’s run the numbers. I estimate the population of the US after 30 to be at least 150,000,000. Out of that only 5 million have AD. So one in 30 develops the disease. Nevertheless, the infection is a risk for cognitive decline in general and AD in particular. The population which best illustrates the validity of Cortexyme’s claim is the Down Syndrome patients incidence of Alzheimer’s. I quote from a paper on the science section of Cortexyme home webpage.
PORPHYROMONAS GINGIVALIS IN ALZHEIMER’S DISEASE BRAINS: EVIDENCE FOR DISEASE CAUSATION AND TREATMENT WITH SMALL-MOLECULE INHIBITORS. SCIENCE ADVANCES, 2019.
In addition, sustained high levels of antimicrobial Aβ driven by chronic P. gingivalis infection of the brain may be toxic to host cells, and therefore, reduction of Aβ levels after treatment of the P. gingivalis infection should be beneficial. Furthermore, Down syndrome (DS), the most common genetic cause of mental disability, has been used to support Aβ as a therapeutic target because of the notably high prevalence of dementia with Alzheimer-type pathology in DS patients (greater than 50% after the age of 60) and the fact that the amyloid precursor protein gene, which gives rise to Aβ, is present on chromosome 21, which is triplicated in DS (65). However, in support of our hypothesis, an aggressive form of periodontitis with rapid progression and onset as early as 6 years of age is associated with DS, but not age-matched normal controls or other mentally handicapped patients of a similar age distribution (66). The occurrence of P. gingivalis has been found to be significant in the subgingival plaque of DS patients beginning around the age of 5 years when compared to age-matched controls, indicating that P. gingivalis abnormally colonizes DS patients in early childhood (67). The reason behind DS patients being susceptible to P. gingivalis infection at such an early age is unclear but may be due to the immunodeficiency that is associated with DS (68). Research is needed to determine whether P. gingivalis and gingipains are present in DS CSF and brain.
In the same paper the authors conclude that:
In summary, we propose that genetic polymorphisms of innate immune system genes in essential immune pathways may result in defective clearance of P. gingivalis and gingipains from the brain, resulting in chronic, low-level infection and neuroinflammation in susceptible individuals.
We are in the middle of Etiology Wars. There might be hundred and one things going on in AD patients physiology, one of them can be the infection with the bacterium which causes periodontal disease. Just beyond natural susceptibility, there might be other mechanism triggering onset of AD. For us, as the investors the most important thing is place our bets on a winning drugs. The AD and dementia etiology is so vast and complicated that it can be already plain to see that few drug at almost the same time are going to emerge as winners. Predicting where the money goes can be even more daunting question. I am not going to touch upon this.
Atuzaginstat (COR388) is the leading drug of Cortexyme. The drug binding to the gingipains thus making them defunct, leaving P. gingivalis infection toothless (pan intended). The infection itself is intact as no antibiotic has been found to reduce the numbers of the bacterium in brain or other colonized tissues. In other words the drugs has to be continuously dosed to have effect. This is going to be difficult to justify unless FDA conditionally approves the drug or a schedule will be given to dosing because there have been a liver reaction to the dosing of the drug over the course of the study (48 weeks). The company claims that these are transitory problems but FDA has put partial clinincal hold on Open Label Extension of the Phase2/3 GAIN study. More information can be found here, link: https://www.cortexyme.com/cortexyme-provides-regulatory-update-on-development-program-for-atuzaginstat-in-alzheimers-disease/.
Even as approved the drug would make it a duty of a physician to check on status of certain liver biomarkers making the drug cumbersome to dose. That in itself can be no surprise as Atuzaginstat binds to P.gingivalis proteases which might be similar to some liver enzymes. On the other hand, would the result in November 2021 (Q4 20121) be good enough and the climate politically accepting of AD drugs the NDA is not out of question.
I run by some notes on other drugs. Upon reading the material from Cortexyme $CRTX I realized that how limited is the terapeutic target of $SAVA. $SAVA Simufilam takes on a side show in the physiology of the AD as Cortexyme papers suggest demage to cytoplasme skeleton, and Simufilam acts on Filamin A cytoplasm skeleton element. The CEO of $SAVA has been awarded $3 million cash, it seems that options would be too long shot for him. One suspects that $SAVA’s result might be not on par. Nevertheless, it could be a good drug to add to drug cocktail a AD patient can use.
Another drug for those who think that infection with P. gingivalis is the way to go is the AVNS401 by Annovis Bio $ANVS. Reference to this can be found in this press release. https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=d75fe079-a291-4623-83a1-7c760a2c8907
It seems that the results from $CRTX are not much different than from $ANVS.
The most interesting is the Winterlight Assessment (Prepositions & Conjunctions) showing real improvements in the use of language in just 28 days. I think it is a more sensitive way to measure some aspects of cognition.
When you compare the results from both studies they seem to agree on the cognition measures like MMSE and ADAS-Cog, but I think that ANVS401 is a better drug as it does not have yet any problems with adverse effect and presents comparable improvements. See Press Realease. To get MMSE scores from ADAS-Cog (rough estimates) divide ADAS-Cog by 2.33. The ANVS401 MMSE score is 1.88 points which is about the same for COR388. Link: https://irpages2.eqs.com/websites/annovis/English/431010/us-press-release.html?airportNewsID=364451b1-06a7-4b96-a389-016f3ef3e6e3
Nevertheless, as it is in the realm of phase2 studies in the Alzheimer’s disease most of them are conducted on samples size so small that the some results are not statistically significant.
I hope that the rally in AD stocks resumes as the uncertainty with FDA approval will be sorted out. There are great many stocks to invested in this field.
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