A growing body of evidence suggests that cardiometabolic risk factors play a significant role in Alzheimer’s disease (AD). Diabetes and hypertension, the famous silent killers, are highly prevalent and can accelerate neurodegeneration and perpetuate the burden of Alzheimer’s disease. Insulin resistance and enzymes including insulin-degrading enzymes are implicated in Alzheimer’s disease where the breakdown of insulin is prioritized over the breakdown of amyloid-β. Studies have shown that immune cells in the brain, particularly microglia, and astrocytes, are key regulators of the inflammatory response in the central nervous system and are involved in the pathogenesis of AD. These cells have various roles, including supporting neurons.

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration associated with synaptic dysfunction and neuronal death, which culminates in brain atrophy. It can also be characterized by the deposition of senile plaques composed of β-amyloid (Aβ) and neurofibrillary tangles (NFTs), formed of hyperphosphorylated Tau protein.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease. The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.

Several clinical trials are testing the effect of Glucagon-like peptide-1 receptor agonists on Alzheimer's patients. For example ISAP clinical trial tests oral semaglutide (Ozempic). Two independent phase 3 trials are already underway, with findings due at the end of 2025. Liraglutide is another glucagon-like peptide-1 (GLP-1) analog currently approved for type 2 diabetes and obesity.

The results of a clinical trial were presented at the Alzheimer’s Association International Conference in the United States. It suggests that liraglutide may protect the brains of people with mild Alzheimer’s disease and reduce cognitive decline by as much as 18% after one year of treatment.

ELAD was a 12-month, multi-center, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 204 participants were randomized to receive either liraglutide or a placebo in a daily injection for a year. The patients with mild Alzheimer’s disease were seen at 24 clinics throughout the United Kingdom. Each received a daily subcutaneous injection for one year: half received up to 1.8 mg of liraglutide and half received a placebo. Before the study began, all patients had magnetic resonance imaging (MRI) to evaluate brain structure and volumes, glucose metabolism PET scans, and detailed memory testing. These were repeated at the end of the study with regular safety visits.

The primary outcome was the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes were the change from baseline to 12 months in scores for clinical and cognitive measures and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes were a 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation, and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group.

ELAD clinical trial was led by Prof. Paul Edison, M.D., Ph.D., professor of science from Imperial College London and probably the most cited author in the field of Alzheimer's research.

While the primary endpoint (change in the cerebral glucose metabolic rate) was not met, scores for clinical and cognitive measures and the exploratory endpoint of brain volume showed statistically significant benefits. The patients who received liraglutide had nearly 50% less volume loss in several areas of the brain, including frontal, temporal, parietal, and total gray matter, as measured by MRI. Patients who received liraglutide had an 18% slower decline in cognitive function in a year compared to those who got the placebo.

Uncomfortable side effects often result from administration of GLP-1 agonists. Here gastrointestinal problems such as nausea were the most common side effects, which totaled 25.5% of all adverse events in the liraglutide group. Twenty-five serious side effects occurred in 18 participants (17.6%) in the placebo arm and seven participants (6.9%) in the treatment arm. The most serious side effects were considered unlikely to be related to the treatment of the study.

Clinical trials are costly, this study was funded by the UK Alzheimer’s Society, Alzheimer’s Drug Discovery Foundation, Novo Nordisk, John and Lucille Van Geest Foundation, and the National Institute for Health and Care Research (NIHR) Biomedical Research Centre.

In conclusion, if these results are confirmed in a phase III clinical trial, they are revolutionary. Indeed they are much better than the recently authorized but controversial drugs that use antibodies to target amyloid plaques.

Yet, this is not a cure, it will slow the disease, not cure it. However no drugs currently slow the disease, and the US-authorized medicines have severe side effects (ARIA).

Adult-onset diabetes is a known risk factor for cognitive impairment and dementia, yet the study of diabetes in young people has been neglected until now.

The average age of onset of diabetes in adults is ~46 years, and roughly thirty years later neurodegenerative diseases may appear. People with early-onset diabetes when they reach the age of 46 years, have lived with their disease for at least 30 years. It is therefore possible that early-onset diabetes leads to early-onset dementia.

A recent prospective population-based cohort in the United Kingdom did find that a younger age at the onset of diabetes corresponded to a younger age at the onset of dementia, but this study did not specifically look at people with early diabetes. A new study on this subject indicates that people with early-onset diabetes are at significant risk of prematurely developing cognitive impairment and dementia with possible neuropathology. This study aimed to explore neurodegenerative disease biomarkers in cohort-derived biomarker banks as changes in key plasma biomarkers between the time of diabetes diagnosis and early adulthood have been correlated with worsening cognitive function in young adults with early-onset diabetes.

Participants with youth-onset diabetes (age of onset less than 20 years) were found in the SEARCH for Diabetes in Youth study, a multicenter population-based registry and cohort. A randomly selected subset of 50 SEARCH participants (n=25 type 1 diabetics, n=25 type 2 diabetics) was identified for inclusion in the plasma biomarker analysis.

Among SEARCH participants eligible for plasma biomarker analyses, the authors recruited and enrolled a subset of the Colorado SEARCH clinic site to complete positron emission tomography (PET) imaging to measure plasma accumulation amyloid and tau density in brain regions susceptible to Alzheimer's disease.

For their study of plasma biomarkers of neurodegeneration, scientists identified age-matched controls without diabetes from two cohorts with plasma samples stored to include adolescent controls from the Exploring Perinatal Study Outcomes in Children (EPOCH) (n = 25) and young adult controls from the CROCODILE (Control of Renal Oxygen Consumption, Mitochondrial Dysfunction and Insulin Resistance) study (n = 21).

The authors also recruited and enrolled a group of young adult controls from the University of Colorado Anschutz Medical Campus to complete PET imaging for amyloid density and tau in brain regions susceptible to Alzheimer's disease.

By studying these two types of biomarkers (plasma and molecular imaging), scientists found evidence of potentially greater neuropathology of neurodegenerative diseases in young adults with early-onset diabetes, where plasma pTau181 was significantly higher and Aβ40 and Aβ42 were significantly lower, compared to controls, and over time from diabetes diagnosis from adolescence to young adulthood.

Furthermore, changes in key plasma biomarkers of neurodegeneration from diabetes diagnosis to early adulthood have been correlated with worsening cognitive function in young adults with early-onset diabetes. These preliminary data suggest the possibility of an early risk trajectory for Alzheimer's disease among individuals diagnosed with diabetes during childhood or adolescence.

It is important to emphasize that the participants with youth-onset diabetes had lower plasma Aβ42 and Aβ40 concentrations than age-matched controls both in adolescence and early adulthood, suggesting amyloid dysregulation potentially early and sustained in diabetes beginning in young people. Lower levels of Aβ40, Aβ42 and their ratio, especially in plasma and cerebrospinal fluid, correspond to monomer sequestration and amyloid plaque formation. Overall, the lower plasma concentrations of Aβ42 and Aβ40 in their sample suggest the development of Alzheimer's disease neuropathology, but could also indicate disrupted neurodevelopment in those with early-onset diabetes.

NfL was not different from controls in adolescence, but was higher on average in the group of young adults with youth-onset diabetes, compared to young adult controls. These results are consistent with other larger studies in adults with diabetes. However, the scientists are cautious in interpreting their NfL results, given that NfL is a non-specific marker of neuronal damage and could also indicate involvement of peripheral neuropathy in people with diabetes. diabetes

The moral integrity of the authors of this study is reflected in the number of limitations highlighted by the authors. Too often, scientists (and their university's public relations department) make overblown, ridiculous, and deliberately misleading claims.

• The young age of their sample limits confounding by age, such that changes in plasma biomarkers are more likely to be attributed to diabetes pathophysiology and not typical aging-related processes.

• Their age-matched control groups were sampled from different cohorts. Thus, scientists cannot interpret biomarker differences between adolescent controls and young adult controls as a typical developmental change in these biomarkers. It should be noted that the shelf life of plasma samples from each group differed, which imposed yet another limitation on their study, with diabetes samples appearing in young people having on average a longer shelf life than control samples. .

Longer storage duration could impact the observed protein concentrations of the measured plasma biomarkers. However, if protein levels were differentially impacted between groups given variability in storage duration, we might expect to see lower concentrations in the youth diabetes group compared to control groups for all proteins measured. This was not the case in their study.

• The scientists did not have APOE4 status among the subjects of their study.

• The SEARCH study did not measure cognitive function at the initial visit so scientists could not study cognitive changes over time in relation to changing plasma biomarker levels.

• Scientists do not have corresponding biomarkers measured in the CSF.

• The sample of young adults with early-onset diabetes who participated in the PET imaging study was small.

In conclusion, although neurodegenerative diseases are conceptualized as a disease of the elderly, increasing evidence suggests that factors linked to early life may have an impact on risk trajectories.

Such life-span course disease models will contribute to a better understanding of how currently used neurodegeneartion biomarkers evolve during critical periods of development across the lifespan, and how they can be used to predict the risk of neurodegenerative diseases early onset and cognitive impairment in high-risk clinical populations such as early-onset diabetes.

The reason we need sleep seems clear: without sleep, we become tired, and irritable and our brain functions less well. Conversely, after a good night's sleep, the brain and body feel refreshed. But why does the brain need to disconnect from the environment for hours every day? What is restored by sleep has proven difficult to explain. Sleep efficiency in older adults. Sleep deprivation increases amyloid-β (Aβ) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aβ. Sleep abnormalities may therefore represent a risk factor for neurodegeneration.

It has recently been shown that sleep is likely a time for clearing waste in the brain or repairing damaged cells. Circadian sleep-wake rhythm disorders are strong predictors of institutionalization.

During a period of wakefulness, coping with the environment requires increasing the number and strength of connections at the synapses between neurons in the brain. This increased activity increases cellular requirements for energy and materials, leading to cellular stress, a major factor in neurodegenerative diseases, and forcing changes in supporting cells such as glial cells, while hindering learning. During sleep, this synaptic activity is decreased which helps restore cellular health and increase plasticity through negative selection of synapses. This may also explain the benefits of sleep for memory acquisition, consolidation, and integration.

In other words, for the theory of synaptic homeostasis, sleep is “the price we pay for our learning and memory abilities”. Increased synaptic activity reduces the selectivity of neuronal responses and limits the ability to learn. By renormalizing synaptic activity, sleep reduces the plasticity burden of neurons and other cells while restoring neuronal selectivity and the ability to learn, and the consolidation and integration of memories.

A new study has just confirmed this, at least in translucent zebrafish larvae. However, these results obtained with zebrafish larvae should only be extrapolated with great caution to humans, but it is nevertheless an interesting discovery for fundamental neuroscience. The study authors used in vivo synaptic labeling tools in larval zebrafish to image the same neurons and their synapses repeatedly over long periods, allowing them to map the synapse changes of a single neuron in states of sleep and wakefulness. In effect, this meant genetically modifying these neurons to allow fluorescence upon firing.

By tracking the synapses of single tectal neurons across sleep-wake states and circadian time, scientists resolve several outstanding questions about the magnitude, universality, and mechanisms of sleep-related plasticity.

They show that synaptic dynamics are present in many cells on average, but when examined neuron by neuron, more diverse patterns of synaptic changes are revealed. These observations may explain some discrepancies between previous studies on the synaptic homeostasis hypothesis, as such single-neuron synaptic dynamics were not captured by one-time snapshots of synapse number or function at the population level.

The authors also found that sleep-related synapse loss depends on molecular signals related to elevated sleep pressure and, notably, also reflects slow-wave activity by occurring primarily at the beginning of the sleep period. This finding raises the question of whether sleep periods associated with low sleep pressure, such as in the second half of the night, play an additional role in non-synaptic remodeling.

Despite all this work was carried out on zebrafish larvae equipped with genetically modified neurons. Thus, any extrapolation to mammals, without even thinking about humans, is highly speculative. Still, it's another clue that sleep is an integral part of good neuronal health, probably along with vascular health and physical activity.

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.