Two very interesting new articles have been published on the (supposed) action of a drug against Alzheimer's disease. These articles provide the reader with several points for further reflection. - One of them is that the clinical trial cannot be the only method of validating the marketing of a drug. Indeed, for diseases that develop over decades, often asymptomatically, how can the effectiveness of a drug be tested? We can always dream of a pill that will cure in a few months a patient, as this is true for diseases where there is an identified pathogen, but it is very unlikely with chronic diseases. Even for communicable diseases, this type of medication does not always exist; a patient can be considered permanently cured, even though they suffer very serious after-effects.

HIV and many other viruses rely on an enzyme, called reverse transcriptase (RT), to copy their RNA molecules and change them into complementary DNA duplicates that can then be inserted back into the host cell's DNA, producing permanent sequence changes.

As RT hijacks a host's cells to establish a chronic infection, so drugs that block the RT enzyme's activity have become a common part of treatment cocktails for keeping HIV at bay.

The team of the first article analyzed anonymized medical records with prescription claims from more than 225,000 controls and patients and found that RT inhibitor exposure was associated with a statistically significant reduced incidence and prevalence of Alzheimer's disease. There were 2.46 Alzheimer's disease diagnoses per 1,000 persons taking these inhibitors, versus 6.15 for the general population. And this with a drug that is not optimized for Alzheimer's disease. Indeed the drugs patients took in this retrospective study were designed to counter a specific form of RT used by HIV and it may only have a limited effect on many different possible forms of the enzyme in the brain. So there is significant room for progress to perfect this drug.

• Another point of reflection concerns the etiology of Alzheimer's disease. This is the subject of numerous debates and gigantic financial bets. Clearly, the pharmaceutical industry ecosystem considers that the appearance of intra and extra-cellular beta-amyloid plaques is the cause of this disease. Few scientists question why these plaques appear, or whether competing hypotheses have been properly studied. In this new article, it is shown that an anti-viral drug significantly reduces the risk of developing Alzheimer's disease.

In a second article, an explanation is proposed as to why clinical trials for this disease most often fail. The amyloid hypothesis, or the theory that the accumulation of a protein called beta-amyloid in the brain causes Alzheimer's disease, has driven Alzheimer's research to date. However, treatments that target beta-amyloid have notoriously failed in clinical trials. The authors of the second article found that most Alzheimer's disease brain samples contained an over-abundance of distinct APP gene variants, compared to samples from normal brains. Among these Alzheimer's-enriched variations, the scientists identified 11 single-nucleotide changes identical to known mutations in familial Alzheimer's disease—a very rare inherited form of the disorder. Although found in a mosaic pattern, identical APP variants were observed in the most common form of Alzheimer's disease, further linking gene recombination in neurons to disease.

“The thousands of APP gene variations in Alzheimer's disease provide a possible explanation for the failures of more than 400 clinical trials targeting single forms of beta-amyloid or involved enzymes,” says Chun. "APP gene recombination in Alzheimer's disease may be producing many other genotoxic changes as well as disease-related proteins that were therapeutically missed in prior clinical trials. The functions of APP and beta-amyloid that are central to the amyloid hypothesis can now be re-evaluated in light of our gene recombination discovery."

• We have all learned that all the cells of an organism have the same genetic heritage since they come from the same original cell. This vision, which dates from the middle of the last century, is beginning to be called into question in different cases: cancers, cases of mosaicism, and aging. These two articles, which come from the same laboratory, raise the question of how to detect these cases of mosaicism. Indeed, if a virus modifies the genome of a cell, but only in certain tissues (such as the brain) and only for a fraction of the cells, a genetic analysis of an easily accessible tissue will not necessarily highlight an alteration of the genome. of a significant fraction of the cell population of another tissue.

The researchers note that: "It is important to note that none of this work would have been possible without the altruistic generosity of brain donors and their loving families, to whom we are most grateful. Their generosity is yielding fundamental insights into the brain and is leading us toward developing new and effective ways of treating Alzheimer's disease and possibly other brain disorders—potentially helping millions of people.

As usual, it is not the first time that RT inhibitors have been proposed against Alzheimer's disease animal models, but it is the first time the effect has been shown in humans.

Atrial fibrillation is a risk factor for stroke and multiple forms of dementia, including Alzheimer’s disease. The exact reasons why atrial fibrillation (a common heart disease) increases dementia risk aren't fully understood, but there are likely several factors involved. Some of these factors directly cause damage, while others increase the chances of getting dementia over time. These factors include tiny blood blockages and bleeding in the brain's small blood vessels. Small strokes you might not even notice, reduce blood flow to the brain, increase long-term inflammation, and lead to shrinkage of brain tissue.

"Silent strokes" seem to be especially important because they're found in up to a quarter of atrial fibrillation patients. In these cases, dementia develops because of damage to the brain's tissues caused by a stroke or a temporary lack of blood flow (transient ischemic attack). So, by preventing these silent strokes, we can also reduce the risk of getting dementia or slow it down. This is why using blood thinners (anticoagulants or anticoagulants) is so important for people with atrial fibrillation.

Catheter ablation of atrial fibrillation is a minimally invasive procedure used to treat atrial fibrillation, a heart condition that causes irregular heart rhythm. Catheter ablation is typically an option for people with atrial fibrillation that is not controlled by medications or who experience significant side effects from medications. It is not a cure for atrial fibrillation, but it can significantly improve symptoms and quality of life for many people.

During the procedure, a thin, flexible tube called a catheter is inserted into a blood vessel in the groin and threaded up to the heart. The catheter uses radiofrequency energy or extreme cold (cryoablation) to create tiny scars on the heart tissue in the areas where the abnormal electrical signals originate. These scars block the faulty electrical signals, preventing them from spreading through the atria and causing irregular heartbeats.

However, studies of atrial fibrillation did not consistently report on the influence of periprocedural anticoagulation and long-term use of anticoagulants on dementia risk.

Swedish scientists evaluated the protective effect of atrial fibrillation ablation in a large cohort who received optimized anticoagulation and compared them with patients whose cases were recorded in the Swedish Patient Register.

They studied the cases of 5,912 patients who underwent first-time catheter ablation for atrial fibrillation between 2008 and 2018 and compared them with 52,681 control individuals from the Swedish Patient Register. The majority of patients were on anticoagulants. The mean follow-up time of those patients in the Swedish Patient Register was 5 years.

The Swedish authors found that catheter ablation and anticoagulation treatment were associated with a lower risk of dementia diagnosis compared with the control group. The result was similar when including patients with a stroke diagnosis, which tends to confirm the vascular origin of these cases of dementia.

These results are in line with similar findings in other countries.

The body's pH level is often stated to become slightly more acidic (below pH 7) as we age, but studies are inconsistent. Ideally, blood pH remains tightly regulated within a narrow range (around 7.4). This is crucial for many bodily functions. It's less clear how the brain's PH is modified with aging and disease. A collaborative research group comprising 131 researchers from 105 laboratories mostly from Japan has published an impressive paper in eLife on the influence of brain pH and lactate levels in neurological disorders. The research group's previous findings in a 2018 small study, suggest that the brain's PH alteration is a consequence of diseases. This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism.

The recent study, suggests that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of diseases, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer's disease. What could be the mechanism between increased lactate and decreased pH? Lactate is a byproduct of metabolism and it is an acid, hence the acidification of pH. Neuronal activity relies heavily on glucose for energy. Under normal conditions, oxygen is readily available, and glucose is broken down through aerobic respiration, producing ATP (energy) with minimal lactate as a byproduct. However, during periods of high neuronal activity or limited oxygen supply, cells shift to anaerobic metabolism, relying more on glycolysis. This process produces more lactate as a byproduct.

These changes were observed in the postmortem brains of patients deceased of several neurological diseases, including Alzheimer's disease. However, the observed phenomena are potentially confounded by secondary factors such as the administration of antipsychotic drugs. In addition, the brains of deceased patients have undergone multiple changes during the transition between life and death, and the conservation process, and these postmortem brains may not reflect the condition of living patients.

This time the authors included autism, epilepsy, bipolar disorder, autism, models of depression, epilepsy, and Alzheimer's disease, as well as peripheral diseases or conditions comorbid with psychiatric disorders (e.g. diabetes mellitus [DM], colitis, and peripheral nerve injury). These animal models included 109 mice, rats, and chick animal models with genetic modifications, drug treatments, and other experimental manipulations such as exposure to physical and psychological stressors. More than 2200 animals were used in a hundred laboratories.

First, this large-scale animal model study revealed that alterations in brain pH/lactate levels can be found in approximately 30% of the animal models examined. 30% is not 100% so more studies are needed to understand this result.

The authors observed no significant correlation between brain pH and age in the wild-type/control rodents. In human studies, inconsistent results have been obtained regarding the correlation between brain pH and age. There isn't necessarily a direct cause-and-effect relationship between aging and altered pH, but rather a decline in the body's efficiency to maintain homeostasis (stable internal environment).

• Reduced Kidney Function: Kidneys play a key role in balancing blood pH by filtering out acids. As kidney function declines with age, the body may struggle to eliminate excess acid: Drink more, and quality water with low minerals!
• Decreased Metabolic Activity: A lower metabolic rate can lead to the buildup of acidic byproducts in the body. Decreased Metabolic Activity manifests itself in slower digestion, heart rate, and breathing, lower body temperature, and reduced strength.

So the authors conclude that if this correlation between brain pH and age, is a feature of disease and not aging, then brain diseases might be instrumental in the appearance of these changes in pH in the brain, but the mechanism of action is far from clear.

Their analysis found that poorer working memory performance in animal models of neuropsychiatric disorders may be predominantly associated with higher lactate levels, which was confirmed in an independent cohort. They found the same result for anxiety, probably because it causes a large increase in brain activity.

In conclusion, this is an excellent study, there are too few studies of that caliber. In the future research will improve the brain's ability to remove lactate. This might involve stimulating transporters that clear lactate from the CNS or potentially using enzyme therapies to convert lactate into other metabolites. Another possibility is with therapies that encourage the brain to rely more on aerobic respiration (oxygen-dependent energy production) as they could minimize lactate production as a byproduct. This could involve optimizing blood flow to the brain or exploring potential metabolic drugs.

Here is another study that announces exceptional results "A daily fiber supplement improved brain function in people over 60 in just 12 weeks!"

The scientists are raving in the press kit: "We are excited to see these changes in just 12 weeks. This holds huge promise for enhancing brain health and memory in our aging population." says first author Dr. Mary Ni Lochlainn from the Department of Twin Research.

Yet other studies have previously shown limited evidence that probiotics may improve cognition in older people with pre-existing cognitive impairment but no clear evidence of the benefit on physical function, frailty, mood, length of hospitalization, and mortality. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515554/ Improving cognition using a simple probiotic would be an extraordinary result due to its simplicity of implementation.

In this study, as in almost all studies, we do not know what led the scientists to test the effect of a molecule. Here the authors wanted to boost the muscle mass of elderly twins (over 60 years old).

Both twins consumed a protein (BCAA) supplement powder, and in one twin from each pair, this was combined with a prebiotic supplement 7.5 g of prebiotic (Darmocare Pre®, Bonsuvan), which consists of inulin (3.375 mg) and fructo-oligosaccharides (FOS) (3,488 mg) and in the other twin from each pair, it was combined with a placebo (maltodextrin). As the products were sent by postal service, it is not known to what extent the treatment was correctly administered. Similarly, it was the patients measured by themselves their performance on the tests. The gender of the patients was not collected but it is assumed as they were elderly patients, that the cohort is majority female.

Stool samples were collected by the participants themselves using the sample collection kits provided. Twins were asked to collect a “pea-sized” stool sample into a DNA/RNA Shield Faecal Collection Tube (Zymo Research), and these were posted to the laboratory.

There is a strong recruitment bias (as usual): Participants were eligible for inclusion if they were aged 60 years or older and had previously reported low dietary protein intake (<1 g/kg body weight/day).

However, when we look at the results, it seems they are very different from what is advertised (as usual).

The results are generally the same in the two groups, with even an improvement in the chair rise test, contrary to what is announced. This improvement is even greater in the placebo group! Could this be attributed to the administration of maltodextrin in the placebo group?

Reviews have concluded that digestion-resistant maltodextrin is classified as a type 5 resistant starch (RS5), a prebiotic dietary fiber having properties that may improve the management of diabetes and other disorders of metabolic syndrome. The action of maltodextrin could be quite similar to that of the BCAAs used in the treatment group.

For the CANTAB test, there is improvement in both groups, but the improvement is greater in the treatment group. However, a standard deviation of 0.83 indicates that the results were indeed highly variable from one patient to the next, highlighting the heterogeneity of responses within the study population.

Furthermore, at the start of the study, the treatment group did not seem to be already impacted by cognitive problems while this was already the case for the placebo group, which raises questions about the objectivity of the random distribution between the two groups.

• For the latency test (response speed) both groups progressed, but the treatment group progressed more.

• For the Spatial working memory test, it is the placebo group that progresses the most!

• For the PAL test: first attempt memory score, it is the treatment group which progresses the most (but as for the previous test both groups progress)

• For the Pattern recognition memory test, both groups progressed, but the treatment group progressed more.

• For the Spatial span (forward span length) test, the treatment group progressed, but the placebo group regressed.

In conclusion, the study announces exceptional results, but the results are minimal, and above all, they may be because the investigators supplemented a group of patients who had been selected as being undernourished with protein. Both groups received compounds that are sugars in the broad sense.

Here is a quick analysis of two recently published papers. One is about the controversial role of 40Hz signals in Parkinson's and Alzheimer's disease, the other is about brain clearance during sleep. Intriguing connections suggest that VIP signaling pathways and EEG activity patterns may contribute to the regulation of brain waste clearance mechanisms during sleep. Indeed further research is needed to explore these interactions comprehensively. The first text discusses the paradoxical activity observed in the brain during sleep, where the brain remains highly active despite the body's restful state.

Scientists from Washington University School of Medicine in St. Louis have discovered that during sleep, brain waves play a crucial role in flushing waste out of the brain. These brain waves, generated by coordinated neural activity, facilitate the movement of fluid through dense brain tissue, effectively cleansing it.

The research indicates that sleep serves as a critical time for the brain to initiate a cleaning process, eliminating metabolic waste and toxins that accumulate during wakefulness. This cleansing mechanism is essential for preventing neurological diseases such as Alzheimer's and Parkinson's, where excess waste buildup leads to neurodegeneration.

The authors demonstrated that neural networks synchronize individual action potentials to create large amplitude, rhythmic, and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow through the brain parenchyma. To demonstrate that the scientists showed that flattening these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. So their study demonstrates that neurons serve as master organizers for brain clearance.

This reminds us of the "40hz" publications that many scientists find controversial.

Funnily another article is published by some of the MIT scientists who told a few years ago that gamma stimulation at a frequency of 40 Hz can reduce Alzheimer's disease progression. The authors of The Picower Institute for Learning and Memory of MIT have now discovered that this stimulation prompts a specific type of neuron to release peptides, which in turn drive processes promoting amyloid clearance via the brain's glymphatic system. This mechanism suggests a potential avenue for treating neurological disorders through sensory stimulation.

The authors from MIT say the relation between the 40hz signals and brain clearance is through interneurons in the brain that express the VIP protein. While named Vasoactive Intestinal Peptide (VIP) because it is first was found to be an intestinal peptide that influences blood pressure and heart rate, it is also expressed in other tissues such as the brain's cortex and hypothalamus.

Brain Clearance and VIP

Vasoactive Intestinal Peptide (VIP) plays a role in modulating various physiological functions in the brain, including neurotransmission and circadian rhythm regulation. Similarly to its action in the intestine on heart and blood flow, studies suggest that VIP is involved in the regulation of cerebral blood flow and may have implications for brain waste clearance mechanisms.

VIP and EEG Brain Waves

VIP-expressing neurons are involved in the regulation of circadian rhythms and are particularly abundant in the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN exhibits rhythmic electrical activity, which influences sleep-wake cycles and may indirectly affect EEG brain wave patterns during sleep. So VIP-mediated signaling pathways may intersect with mechanisms regulating EEG brain waves and brain clearance processes during sleep. VIP's role in modulating neural activity and circadian rhythms may influence the generation of EEG patterns associated with sleep stages, which, in turn, could impact glymphatic clearance and waste removal in the brain.

As usual, don't expect fast progress if this therapy hits the market, months of chronic sensory gamma stimulation may be needed to have sustained effects on cognition.

This post is about an interesting hypothesis. Hypotheses abound, yet few a convincing.

Half of patients with Alzheimer's disease, Parkinson's disease, or ALS have insulin resistance. Obesity and diabetes have been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). This means the cells of their body cannot let the glucose enter them. Glucose is the main energy source as it is converted into ATP. Glucose is for short-term (day) energy needs. Another source of energy is lipids (fat). Lipids are even more dense than glucose energy-wise.

The body needs an enormous amount of energy. With all the lipids in the body of a healthy person, you could charge two Tesla cars! The brain (a part of the CNS) needs 20% of all energy intake.

A new paper argues that cells shift their metabolism from glucose to lipids under stressors. It tells that one notable distinction between glucose and lipid metabolism is in the quantity of oxygen required to generate each ATP molecule. Lipid metabolism needs two times more oxygen than glucose metabolism. The result is two times more damaging ROS (a by-product of metabolism). Studies have shown that oxidative stress and endoplasmic reticulum stress are correlated and can lead to protein misfolding (Abramov et al., 2020). Accumulation of misfolded proteins causes cellular damage and mitochondrial dysfunction and is associated with a range of neurodegenerative diseases, including ALS (misfolded SOD1, TDP-43, C9orf72) (McAlary et al., 2020), Parkinson's disease (misfolded α-synuclein) and Alzheimer disease (misfolded Aβ and Tau) (Abramov et al., 2020).

It explains also the accumulation of iron in patients' brains: To transport oxygen the blood cells need iron, and as the glucose in the blood is not absorbed in cells, it induces a change in microbiota.

It's also well known that SCFAs (including butyrate) have a positive effect on neurodegenerative diseases by their action on microbiota. SCFAs help to restore glucose as the preferred energy substrate. Authors say there are other means to restore glucose as the main source of energy.

What to think about this paper? First, some authors belong to a biotech so we can expect they want to promote their drug: Mitometin. Second, this is a review, this is not even a pre-clinical study, yet some of the authors were involved in pre-clinical studies on this topic. Other groups have written on this topic. What to make of this? Acetyl-CoA carboxylase might be of interest as they produce malonyl-CoA which inhibits the CPT1 gene that regulates lipid metabolism. B7 vitamin is known to convert acetyl-CoA to malonyl-CoA for fatty acid synthesis.

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.