A Rare Gene Mutation Offers Clues to Combating Alzheimer’s and Cancer

The human immune system is not only our first line of defense against infectious threats, but it also plays an essential role in regulating how our bodies respond to internal dangers like cancer and neurodegenerative diseases.

One of the immune system’s tools is a molecular pathway known as cGAS-STING. This pathway functions as a sensor, detecting misplaced DNA in cells — a common feature in viral infections, cancer transformations, and some brain disorders.

A rare genetic mutation, first observed in 2019 in a woman with a strong inherited risk for Alzheimer’s disease, may help us better understand and even treat conditions such as Alzheimer’s, cancer, and autoimmune disorders. This woman, who carried a high-risk PSEN1 mutation that usually causes early-onset Alzheimer’s, remained cognitively intact into her seventies. Postmortem analysis revealed extensive amyloid plaques in her brain (a hallmark of Alzheimer’s) but very low tau pathology, which is more closely linked to memory loss and cognitive decline.

Genetic testing showed she carried two copies of a rare variant of the APOE3 gene: R136S, also known as the Christchurch mutation. APOE is a gene long known to influence Alzheimer’s risk, with different variants (APOE2, APOE3, and APOE4) conferring varying levels of protection or susceptibility.

What roles does the cGAS-STING pathway play? Under normal conditions, our cells keep their DNA tightly stored in the nucleus. But sometimes, DNA ends up in the wrong place — floating in the cytoplasm, the main body of the cell. This can happen due to viral infection, cellular stress, or genetic damage. The immune system interprets this misplaced DNA as a danger signal.

cGAS acts as a sensor activated primarily in two pathological contexts: microbial invasion by DNA viruses, bacteria, or retroviruses that introduce exogenous DNA into the cytoplasm, and aberrant leakage of nuclear or mitochondrial self-DNA into the cytosol. When cGAS detects double-stranded DNA in the cytoplasm, it produces a signaling molecule called cGAMP. This molecule then binds to a protein called STING (stimulator of interferon genes), activating a cascade that results in the production of type I interferons and inflammatory cytokines. These signals alert the immune system to potential threats and mobilize a defensive response. Interestingly, TDP-43, which is involved in several degenerative diseases, also has roles in protecting against DNA damage and viruses such as HIV.

While this response is critical for fighting infections and catching early-stage tumors, it can also become problematic when overactive. Persistent or misdirected cGAS-STING activity has been linked to autoimmune diseases, chronic inflammation, and cellular aging (senescence).

New Insights from Mouse Models To explore how exactly the R136S mutation offers protection, researchers engineered mice with human APOE3 or APOE3-R136S genes and introduced a tauopathy-causing mutation (P301S) mimicking key features of Alzheimer’s and frontotemporal dementia.

The findings were compelling: Mice carrying the R136S mutation showed less tau buildup, fewer signs of synaptic and myelin loss, and better brain activity patterns (theta and gamma oscillations important for learning and memory).

At the molecular level, the R136S mutation suppressed the cGAS-STING pathway in microglia, the brain’s resident immune cells.

When researchers treated APOE3 mice (a model of Alzheimer's) with a cGAS inhibitor, these animals exhibited many of the same benefits seen in people who are R136S carriers, including protection from tau-induced synaptic damage and similar gene expression changes across multiple brain cell types.

cGAS-STING: From Immunity to Neurodegeneration This research highlights a key insight: overactivation of cGAS-STING in microglia plays a damaging role in tau-driven neurodegeneration. Misfolded tau proteins can cause inflammation and disrupt brain networks, and microglia that respond too strongly—especially by ramping up interferon signaling through cGAS-STING—may inadvertently worsen the damage.

By reducing this response, the R136S mutation appears to create a more balanced immune environment in the brain. Instead of amplifying harmful inflammation, microglia can more effectively process and break down tau.

The discoveries related to R136S and the cGAS-STING pathway have broad implications:

• Cancer Immunotherapy: The same pathway that detects misplaced DNA in Alzheimer’s also helps identify cancer cells. Modulating cGAS-STING could improve immune responses against tumors or reduce chronic inflammation that promotes their growth.
• Autoimmune Disorders: Conditions like Aicardi–Goutières syndrome involve constant activation of the cGAS-STING pathway, leading the body to attack itself. Understanding how mutations like R136S impact this response may aid in developing treatments that dial down harmful immune activity without compromising protective responses.
• Healthy Aging and Senescence: The cGAS-STING pathway is also involved in cellular aging and the development of the senescence-associated secretory phenotype (SASP). Inhibiting this pathway could delay age-related degeneration and lessen age-related inflammation.

Looking Forward: From Mutation to Medicine

As discussed above, reducing cGAS-STING activity carries risks, including the potential to increase cancer susceptibility in older adults. Additionally, effects may vary across different cell types, benefiting the brain while impairing other vital organs. There are multiple schools of thought about what causes Alzheimer's disease; some incriminate the tau protein, but a majority of researchers are working on mitigating amyloid plaques. Another consideration —though obvious but not often explicitly stated— is that this research provides a preventive tool against Alzheimer's disease. In its early stages, it may slow the disease's progression, but it cannot cure someone who experiences the full impact of the disease.

In conclusion, the cGAS-STING pathway is a crucial sensor of misplaced DNA and a regulator of immune responses. A rare mutation in APOE3 (R136S) has been shown to suppress this pathway in brain immune cells, protecting against tau-related damage in Alzheimer’s models. This discovery opens new avenues for treating neurodegenerative diseases, autoimmune disorders, and cancer through precise modulation of our immune system’s ancient alarm system.

Recent research continues to highlight the complex relationship between cardiovascular health and brain aging. For instance, vascular dementia is one type of dementia. Furthermore, universities are encouraging their teams to identify useful biomarkers for neurodegenerative diseases, as they believe they can generate revenue from potential patents. One quick and inexpensive method to conduct a study is to utilize databases available online.

The Framingham Study is a long-term epidemiological study (since 1948) that initially focused on cardiovascular disease. We owe much of our knowledge about cardiovascular disease to the Framingham Study, particularly regarding the identification of cardiovascular risk factors, including the effects of smoking and diet. Thus, the recognition of high blood pressure as a risk factor for heart disease dates back to 1957, for neurological diseases to 1967, and heart failure to 1971. By Manu5 - http://www.scientificanimations.com/wiki-images/

At the same time, the Framingham Study focused on a relatively affluent population of European origin, meaning the conclusions drawn from it may not necessarily apply to other populations. Furthermore, marker values vary depending on the data collection devices and methods (some values date back to 1948!), so an a priori analysis must consider these difficulties, which is rarely addressed in rapid studies.

The authors of the article discussed in this post selected 822 elderly individuals (mean age: approximately 72 years) from the database who were not suffering from dementia at the time of their first blood test with the Framingham Study. Participants were monitored for Alzheimer's disease until 2020. Over a median follow-up period of 12.5 years, 128 of these individuals developed Alzheimer's disease.

The article authors measured levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL cholesterol (sdLDL-C), lipoprotein a (Lp(a)), apolipoprotein B (ApoB), and the ApoB48 isoform of ApoB in the blood samples collected from 1985 to 1988 by the Framingham Study.

It has long been acknowledged that, although the mechanism is not fully understood, elevated levels of apolipoprotein B (ApoB) are associated with higher concentrations of LDL particles and are the primary driver of plaques that cause vascular disease (atherosclerosis), which typically first manifests as obvious symptoms such as heart disease, stroke, and various other body-wide complications after decades of progression.

Furthermore, the causes of Alzheimer's disease remain poorly understood, but the most significant genetic risk factor arises from an allele of apolipoprotein E. Other risk factors include a history of head trauma, clinical depression, and high blood pressure. The progression of the disease is largely characterized by the accumulation of malformed protein deposits in the cerebral cortex, known as amyloid plaques and neurofibrillary tangles.

Therefore, there is a possible link between dementia and cardiovascular risk, and the Framingham Study database allows us to statistically compare heart health and the risk of developing comorbidities.

The article authors considered a wide range of cholesterol-related markers:

• HDL-C: "Good" cholesterol

• LDL-C: "Bad" cholesterol

• sdLDL-C: Small, dense particles of LDL cholesterol

• ApoB and ApoB48: Proteins involved in cholesterol transport

• Lp(a): A lipoprotein linked to the risk of heart disease

The researchers examined the relationship between these markers, standardized by their standard deviation units (SDUs), and the future risk of Alzheimer's disease.

** sdLDL-C ** They found that high sdLDL-C levels correlate with an increased risk of developing Alzheimer's disease. This result has also been observed by other teams, including a recent one that examined a database in Finland:

SdLDL-C stands for "small dense low-density lipoprotein cholesterol." It is a subclass of LDL particles that are smaller and denser than conventional LDL and more likely to penetrate blood vessel walls. This cholesterol subtype is rarely tested. sdLDL is regarded as a more atherogenic lipoprotein due to its higher retention rate in the arterial wall, better penetration, lower binding affinity to the LDL receptor, lower resistance to oxidative stress, and longer plasma half-life. In addition to being associated with a heightened risk of cardiovascular disease, sdLDL, particularly sdLDL-C levels, have been linked to type 2 diabetes mellitus, metabolic syndrome, obesity, and low-grade inflammation.

** ApoB48 ** Conversely, elevated ApoB48 levels are linked to a reduced risk of Alzheimer's disease. This finding was previously known.

** HDL-C ** However, the authors uncovered surprising results regarding HDL-C, often referred to as "good cholesterol". Numerous epidemiological studies have indicated that high circulating HDL levels are associated with a reduced risk of Alzheimer's disease. Yet, this new study's authors found that participants with the lowest HDL-C levels had a 44% reduced risk of developing Alzheimer's disease compared to those with higher HDL-C levels.

Because HDL-C is generally considered protective, this team's findings may reflect other age-related changes, such as metabolic status or weight loss, that occur before the onset of dementia.

Un article semble démontrer de façon inattendue que certains médicaments contre le VIH et l'hépatite pourraient contribuer à réduire le risque de maladie d'Alzheimer. La maladie d'Alzheimer (MA) reste l'une des maladies les plus complexes de la médecine moderne, tant en termes de traitement que de prévention. Mais des recherches par une équipe de l'université de Virginie menée par Joseph Magagnoli et Meenakshi Ambati, pointent vers un allié potentiel inattendu : une classe de médicaments antiviraux initialement développés pour traiter le VIH et l'hépatite B.

On sait que réduire l'inflammation induite par NLRP3 peut réduire l'impact de la maladie d'Alzheimer. Les inhibiteurs nucléosidiques de la transcriptase inverse (NRTI), sont approuvés par la Food and Drug Administration (FDA) des États-Unis pour traiter les infections par le virus de l'immunodéficience humaine (VIH) et l'hépatite B. L'équipe de Joseph Magagnoli et Meenakshi Ambati avait montré antérieurement des NRTI inhibent également l'activation de l'inflammasome indépendamment de leur activité antirétrovirale. D'autres groupes ont par la suite confirmé cette observation.

Cependant il s'agit là des études pré-cliniques, il y en a des dizaines de milliers chaque année pour la maladie d'Alzheimer et elles ne suffisent pas à convaincre un investisseur de financer une étude clinique qui en phase III coûte au minimum une vingtaine de millions de Dollars. Il faut donc des indications qu'un tel médicament pourrait bénéficier à de spatients humains. Plusieurs moyens peuvent être employés, mais si l'on veut prouver qu'un médicament déjà commercialisé est utile dans une autre maladie, il est intéressant d'étudier les bases de données historiques qui analyse l'évolution d'une cohorte sur une longue période.

Les chercheurs ont analysé deux importantes bases de données de santé américaines afin de répondre à une question simple, mais essentielle : les personnes prenant des inhibiteurs nucléosidiques de la transcriptase inverse (NRTI), un groupe de médicaments antiviraux, présentent-elles un risque moindre de développer la maladie d'Alzheimer ?

Les chercheurs ont examiné plus de 270 000 patients dans deux bases de données : - Administration de la santé des anciens combattants (VA) – 72 193 patients entre 2000 et 2024 - MarketScan (assurance privée) – 199 005 patients entre 2006 et 2020

L’étude a porté sur des personnes âgées de 50 ans ou plus, atteintes du VIH ou d’hépatite B, mais sans diagnostic préalable de maladie d’Alzheimer. L’étude a permis de déterminer les personnes à qui des NRTI étaient prescrits et la durée de leur prise.

L’analyse a pris en compte un large éventail de facteurs susceptibles d’influencer le risque de maladie d’Alzheimer, notamment l’âge, le sexe, l’origine ethnique, les maladies cardiaques, le diabète, la dépression, les lésions cérébrales, etc. Les chercheurs ont également réalisé une analyse spécifique (appelée appariement par score de propension) afin de s’assurer de comparer des groupes de personnes similaires : celles qui prenaient des NRTI et celles qui n’en prenaient pas. Ils ont confirmé qu'une exposition prolongée aux NRTI était associée à un risque moindre de développer la maladie d’Alzheimer. - D’après les données du VA, chaque année supplémentaire de traitement par NRTI était associée à une réduction de 4 à 6 % du risque de maladie d’Alzheimer. - D’après les données de MarketScan, la réduction était encore plus marquée : de 10 à 13 % par année d’utilisation.

Au total il semblerait que la prise d’un NRTI soit associée à une réduction de 32 à 37 % du risque de maladie d’Alzheimer. Attention il s'agit bien de réduction du rique de développer cette maladie, il ne s'agit pas d'un médicament qui guérirait de cette maladie. Une question importante est alors (si ce médicament est autorisé) sur quels critères devrait-on prescrire ce médicament à des personnes apparement saines?

Il s’agit d’une étude observationnelle et non d’un essai clinique ; elle ne prouve donc pas que les NRTI préviennent la maladie d’Alzheimer. Mais la concordance des résultats obtenus sur deux grandes populations, avec des ajustements importants pour d'autres facteurs de santé, rend ces conclusions remarquables.

Ce qui est particulièrement intriguant, c'est que les NRTI sont déjà approuvés et utilisés, ce qui signifie qu'ils pourraient être réutilisés plus rapidement que des médicaments entièrement nouveaux. Et comme la maladie d'Alzheimer est une maladie aux options thérapeutiques limitées, même de petites avancées en matière de prévention pourraient faire une différence significative.

Des essais contrôlés randomisés, sont nécessaires pour confirmer si ces médicaments ont réellement un effet protecteur contre la maladie d'Alzheimer et si ce bénéfice l'emporte sur les risques, en particulier chez les personnes non atteintes du VIH ou de l'hépatite B. Néanmoins, cette recherche ouvre une voie prometteuse.

Researchers are currently very interested in finding biomarkers for the early detection of many neurodegenerative diseases. The market for these technologies is likely to be quite large. Detecting weakened cerebral rigidity before the onset of irreversible damage could pave the way for early intervention in Alzheimer's disease and related disorders. This could be achieved using a device that has now become relatively common: MRI. The hippocampus, a small, seahorse-shaped structure buried deep within the brain, is best known for its role in memory formation and learning. It is an exceptionally vulnerable structure, with perfusion deficits often observed in diseases related to learning and memory. However, a brain affected by Alzheimer's disease tends to exhibit at least moderate cortical atrophy, including in the precuneus and posterior cingulate gyrus. It should be noted that the posterior cingulate gyrus is adjacent to the hippocampus.

A recent study shows a relationship between blood flow and mechanical stiffness (an MRI concept) of the hippocampus. Researchers sought to understand how these physical properties interact in a healthy brain and what this might reveal about early brain changes in neurodegenerative diseases. The researchers used two advanced MRI techniques—magnetic resonance elastography (MRE) and arterial spin labeling (ASL).

Using these tools, the researchers measured: * Tissue stiffness (the resistance of an area to physical deformation) * Perfusion (blood flow at the tissue level)

Seventeen healthy adults were examined by the researchers at two different MRI intensities (3T and 7T), allowing for a cross-comparison between the two magnetic field strengths. They found that the hippocampus had the highest blood flow among the deep gray matter structures, followed closely by the caudate nucleus and putamen.

A strong positive correlation was observed between blood flow and stiffness in the hippocampus, but not in the caudate nucleus, although both regions are highly vascularized. This indicates that good brain health appears to be linked to good blood flow, manifested by the good stability (stiffness) of the tissue.

In a subgroup of ten subjects, it was found that higher blood flow resulted in larger tissue pulsations, suggesting that the dynamics of blood supply physically influence the hippocampus.

These results suggest a previously underestimated link between the physical characteristics of well-perfused brain tissue and its metabolic needs. This connection is not entirely surprising, as the macroscopic characteristics of tissue depend on the well-being of its constituent cells.

Although not mentioned in the article, one might wonder about the relationship between this mechanical property—rigidity—and beta-amyloid (Aβ), the signature protein implicated in Alzheimer's disease.

Beta-amyloid plaques begin to accumulate in the brain well before the onset of symptoms. These plaques can form: * Extracellularly: outside neurons, interfering with cell-to-cell communication and nutrient supply; * Intracellularly: inside neurons and other nerve cells, disrupting protein production.

Based on current knowledge, beta-amyloid likely appears before physical changes in tissues. It emerges early, sometimes decades before cognitive symptoms, triggering a cascade of tissue changes. Mechanical stiffness, as measured by MRE, is more likely a result of these changes than a cause.

Interestingly, numerous MRE studies have observed brain softening, particularly in the hippocampus and cortex, in Alzheimer's patients and those with mild cognitive impairment. This supports the perspective that stiffness decreases due to beta-amyloid pathology and its effects on brain tissue structure.

As fascinating as these findings are, it is important to acknowledge the limitations of the study, which suggest future research directions.

With only 17 participants, the study lacks statistical power, making it vulnerable to false positives or exaggerated effect sizes.

All subjects were young adults (22–35 years old) who were generally healthy, limiting the relevance of the results to aging populations or those at risk for Alzheimer's disease.

The sample did not include key groups, either clinical or high-risk individuals, such as APOE4 gene carriers or those with mild cognitive impairment (MCI).

The study was cross-sectional, capturing a single snapshot in time. We do not yet know how stiffness or perfusion might change over time or in response to pathology.

No cognitive data were collected; therefore, the relationship between hippocampal mechanics and actual memory performance remains unexplored.

There are considerable interpretation challenges: Stiffness, measured by magnetic resonance elastography (MRE), reflects a complex array of biological factors: neuronal density, inflammation, vascular integrity, etc. It is a valuable signal, but not biologically specific. Indeed, perfusion can vary depending on common physiological factors (e.g., hydration, stress).

Because the study did not include beta-amyloid PET scans or fluid biomarkers, the link between mechanical findings and Alzheimer's pathology remains hypothetical.

The analysis focused on the hippocampus and a few other deep gray matter structures. Key cortical regions involved in Alzheimer's disease (such as the entorhinal cortex or precuneus) were not examined.

The emerging link between perfusion and mechanics, and how this relationship deteriorates in the presence of beta-amyloid, could help us uncover subtle clues that precede cognitive decline. Ultimately, measuring something as simple as brain "firmness" could help us identify those at risk and determine when to act.

An interesting research article was recently published on bioenergetic subgroups in Alzheimer's Disease. The study found a connection between acylcarnitines, bioenergetic age, and Alzheimer's progression. It opens up interesting possibilities for how we might approach brain health from a metabolic perspective as the study suggests brain health to be largely modifiable rather than genetically determined. Focusing on general metabolic health through evidence-based approaches like regular exercise, quality sleep, and dietary patterns that support mitochondrial function could potentially be beneficial. The researchers used acylcarnitine profiles from blood samples to identify distinct bioenergetic subgroups in Alzheimer's Disease (AD) patients and evaluate how bioenergetic capacity relates to disease progression. They used data from 1,531 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), and identified several bioenergetic subgroups with significant differences in AD biomarkers, cognitive function, and brain glucose metabolism. These subgroups were primarily determined by modifiable factors (40-60%) related to beta-oxidation function, rather than genetic factors, suggesting potential for intervention.

The researchers developed a "bioenergetic age" metric based on acylcarnitine levels that strongly correlated with AD pathology. Individuals with "younger" bioenergetic ages showed less severe disease markers. Baseline bioenergetic age predicted cognitive decline over time in multiple studies, independent of APOE ε4 status in most cases. Specific genetic variants (SNPs rs17806888 and rs924135) influenced cognitive decline trajectories, but their protective effect appeared limited to individuals with younger bioenergetic ages. A simulated clinical trial showed that individuals with younger bioenergetic ages had significantly better outcomes on multiple clinical measures, with effect sizes comparable to those seen in the lecanemab anti-amyloid antibody trial.

The research suggests that targeting bioenergetic capacity could be a promising intervention approach for AD, particularly for the approximately 30% of individuals with protective genotypes but older bioenergetic ages.

In addition to the usual recommendations (Exercise/physical activity, dietary approaches, sleep optimization, stress reduction) supplementation (with medical supervision) might be an option:

• L-carnitine/acetyl-L-carnitine - directly involved in fatty acid transport for beta-oxidation
• Omega-3 fatty acids - support mitochondrial membrane health
• Coenzyme Q10 - important for mitochondrial energy production

Today there isn't a widely available, inexpensive rapid test specifically for comprehensive acylcarnitine profiling that consumers can easily access. Yet your doctor could order acylcarnitine profiling, though it's not a routine test. Some companies offer more comprehensive metabolic panels that include some acylcarnitine measurements, though these typically cost $300-500+ and aren't widely validated. There's no equivalent to something like a glucose meter or rapid cholesterol test for measuring acylcarnitines at home or in point-of-care settings.

Here is a paper that outlines a new theory on the cause of Alzheimer's disease with implications for Parkinson's disease as well as ALS.

This is just speculation, based on almost only one fact: The expression of many genes is involved in this disease, so it would imply a global deregulation of the cellular machinery. Unfortunately, as usual in biology, this is a purely qualitative theory and, therefore, susceptible to many possibly contradictory interpretations. However, it is a theory that sees many neurodegenerative diseases as belonging to a spectrum rather than as distinct diseases. I endorse this point of view. Alzheimer's disease research has produced many hypotheses over the years, including cholinergic, inflammatory, viral, mitochondrial, tau, and amyloid. However, none of these hypotheses have led to treatments that can stop or reverse the disease. This leads to a search for new theories to explain these failures. But this may be because interventions occur too late in the disease progression, with brain damage irreparable and compensatory mechanisms saturated.

Most publications ignore physiology, such as the importance of drainage in the cerebral lymphatic channels that have been discovered in recent years. This publication is no exception to this unfortunate trend, it is a discussion of the functioning of a cell in general, not even a brain cell like a neuron or an astrocyte, and the theory is even mostly not specific to humans or mammals, which still leaves one very skeptical. In this publication, the authors suggest that a disrupted nucleocytoplasmic transport system, linked to the formation of stress granules (SG), plays a central role. Cellular stress itself can have multiple causes independent of each other. There is no clear explanation why a general blockage of the cell would specifically lead to the appearance of beta-amyloid in Alzheimer's disease, nor that of alpha-synuclein in Parkinson's disease or TDP-43 in ALS.

In this model, cellular stress triggers SGs, which disrupt the movement of molecules between the nucleus and the cytoplasm, affecting RNA transport, chromatin accessibility, and alternative splicing. These changes lead to synaptic dysfunction, metabolic disorders, protein processing defects, and ultimately cell death. When this process propagates to brain regions, it results in clinical Alzheimer's disease.

The authors present a multistep mechanism linking SGs, NCT dysfunction, and amyloid propagation: * SG formation disrupts nucleocytoplasmic transport, altering gene expression and RNA localization. * Aβ clearance is decreased due to impaired lysosomal function, reduced proteostasis, and disrupted Aβ export. * Aβ production may increase via impaired APP processing. * Seeding and spreading of Aβ aggregates are facilitated by exosome dysregulation and chaperone sequestration. * Glial activation and BBB dysfunction further enhance Aβ diffusion in the brain.

The mention of ALS, FTD, and other conditions with similar transport disruptions strengthens the model's plausibility by showing how dysfunction of nucleocytoplasmic transport is implicated in multiple diseases.

Eukaryotic cells regulate the movement of molecules between the nucleus and the cytoplasm through nuclear pore complexes (NPCs), which are composed of nucleoporins. This transport is controlled by importins, exportins, and the protein Ran, which provides the energy for molecular movement.

Stress granules (SGs) are nonmembranous cytoplasmic structures that form in response to cellular stress, typically through phosphorylation of eukaryotic initiation factor 2 (eIF2α). During transient stress, SGs help cells recover, but during chronic stress, such as in Alzheimer's disease (AD), SGs abnormally persist and sequester key molecules, disrupting transcription and nucleocytoplasmic transport.

Disruption of nucleocytoplasmic transport in Alzheimer's disease (AD) was first reported in 2006, when cytoplasmic accumulation of nuclear transport factor 2 (NTF2) was observed in hippocampal neurons, even before the formation of neurofibrillary tangles (NFTs). This suggests that dysfunction of the transport system occurs early in the progression of AD. Analysis of gene expression data shows similar transport-related disruptions in tangle-bearing and non-tangle-bearing neurons.

Similar disruptions are observed in ALS, FTD, Huntington's disease, and even in non-neurological diseases such as cancer and heart failure. However, the specific transport disruptions vary by disease, likely due to different patterns of SG sequestration.

Some neurons maintain normal expression of the transport system and show enrichment in translational and neuronal function pathways, while others, with altered expression of the transport system, display stress-related pathways and deficits in mitochondrial function and metabolism. These findings are consistent with in vitro studies, suggesting that AD progresses along a continuum at the cellular level, ultimately leading to widespread neuronal dysfunction and clinical symptoms.

Conclusion The text suggests a causal role for SGs and transport dysfunction in AD, but much of the available supporting evidence comes from in vitro studies or studies of related diseases (e.g., ALS, FTD). The available direct in vivo evidence demonstrating SG-mediated pathology in AD patients is still limited.

Although the text discusses tau tangles and Aβ, their role appears secondary to SGs. Since amyloid and tau pathology remain at the core of AD research and therapeutic efforts, their relative downplaying constitutes a potential weakness.

The proposed model is primarily based on molecular and cellular studies, with little reference to clinical data.

In recent days, there has been a lot of talk on social networks and mainstream press about a surgical procedure that is being carried out in a Shanghai hospital by a team led by Li Xia from the Faculty of Medicine of Shanghai Jiao Tong University, which could slow the progression of Alzheimer's disease, or even allow a temporary regression, in half of the participants.

Five weeks after the operation, clinical assessments revealed an improvement in cognitive function: the Mini-Mental Status Examination score went from 5 to 7, and the Clinical Dementia Rating-sum of boxes test score went from 10 to 8. The Geriatric Depression Scale score went from 9 to 0. The PET scan examination provided objective proof of this improvement.

This recent increase of interest is quite curious because a publication was made in June of this year by the team that innovated with this technique.

This study presents a new surgical procedure, neck shunting to unclog the cerebral lymphatic systems, aimed at improving the elimination of waste accumulated in the glymphatic system of the brain to manage Alzheimer's disease. The glymphatic system facilitates the removal of harmful proteins such as beta-amyloid and tau, the accumulation of which is linked to Alzheimer's disease.

The surgical procedure uses lymphatic-venous anastomosis (LVA) to decompress the cervical lymphatic trunk, allowing cerebrospinal fluid (CSF) and residual proteins to flow more efficiently from the brain into the venous system.

It is an extracranial procedure and therefore less invasive and potentially safer than intracranial methods. The surgical treatment, which involves four small incisions in the patient's neck, has been performed on at least 30 patients in two public hospitals in China. Other much larger numbers of patients treated are circulating on the Internet.

Early results indicate that the procedure holds promise as an innovative strategy for the prevention and treatment of Alzheimer's disease.

This surgical technique has not been considered for the treatment of Alzheimer's disease, or even the brain in general, but has been used for some time for other diseases such as lymphedema.

The field of lymphedema surgery has seen enormous progress over the years and has been associated with the rapid growth of super microsurgery techniques. A lymphovenous bypass or lymphaticovenular anastomosis requires the identification of residual lymphatic channels and the creation of an anastomosis on a recipient venule, thus allowing the flow of lymphatic fluid and the improvement of a patient's lymphedema.

A technique similar to that of Chinese doctors has long been used in the context of hydrocephalus. The cause of this disease is a blockage of cerebral-spinal fluids which leads to an accumulation of these fluids in the brain. Treatment for hydrocephalus then involves creating a way to drain the excess fluid from the brain.

In the long term, some hydrocephalus patients require a permanent cerebral shunt. This involves placing a ventricular catheter (a silastic tube) into the brain's ventricles to bypass the flow obstruction and drain the excess fluid into other body cavities, where it can be reabsorbed. Most shunts drain fluid into the peritoneal cavity (in the abdomen), but other sites include the right atrium (heart), pleural cavity, or gallbladder.

Hydrocephalus is known to cause Alzheimer's disease. Normal pressure hydrocephalus is common in elderly patients. Curiously, as Western physicians consider this hydrocephalus to be independent of Alzheimer's disease they are reluctant to operate on these patients because they believe the benefits are small.

The Chinese approach is the opposite. She believes that this accumulation of cerebrospinal fluid in Alzheimer's disease should be treated because, at the very least, it can temporarily relieve about two-thirds of patients. This pragmatic approach considers the patients and does not seek to demonstrate whether or not this accumulation causes Alzheimer's disease.

In a series of videos posted last month on social media, Cheng Chongjie, a doctor in Chongqing who adopted the technique following his colleagues, said the operation was effective in more than half of his patients.

"Two national medical centers have performed hundreds of LVA operations, and their results show that this procedure is effective in 60 to 80 percent of patients.

In the case of neurodegenerative diseases, it is certainly more useful to try to develop new neuronal cells than to "cure" cells that we are told are dying or even dead for months. This is the purpose of regenerative medicine.

One of the difficulties is that neurons are cells that do not reproduce, we live with the stock that we had at the end of our puberty. These cells come from stem cells.

In our brain and the rest of the central nervous system, half of the cells are not neurons, but more classic cells that nourish and maintain neurons.

These cells reproduce by fission like most cells. In particular, astrocytes, although tiny, have many points in common with neurons. It is therefore natural to want to transform astrocytes into neuronal stem cells. Curiously, scientists are rather looking to directly convert astrocytes into neurons, despite the enormous morphological difference between these two types of cells.

A few years ago, following the discovery of Yamanaka factors, it was believed that this goal could be achieved quickly. However, the results obtained have been contested, in particular, because of methodological flaws. Despite the promising results of previous studies, the lack of robust lineage tracing methods has led to uncertainty as to whether the induced neurons originated from glial cells or whether native neurons were mistakenly labeled.

A new publication describes recent advances in converting glial cells into induced neurons in the central nervous system, particularly in regions where stem cell activity is limited. The previous “lineage reprogramming” approach used transcription factors to change the identity of terminally differentiated cells, such as glial cells, to other cell types.

The current study focuses on the transcription factor Ascl1, known for its role in neuronal fate decisions and its potential to reprogram various cell types into neurons. While Ascl1 can efficiently convert glial cells into induced neurons in vitro, its efficacy in vivo varies widely, often leading to limited neurogenic effects or, in some cases, inducing glial proliferation rather than neuronal conversion.

This inconsistency suggests that regulatory challenges affect Ascl1’s performance as a reprogramming factor, particularly due to context-specific modifications such as phosphorylation, which modulate its activity. Previous research has found that a mutant variant of Ascl1, known as Ascl1SA6, engineered to resist phosphorylation, enhances neurogenic activity, prompting this study to determine whether Ascl1SA6 could enhance glia-to-neuron reprogramming in vivo.

The researchers tested Ascl1SA6 in the early postnatal mouse cerebral cortex, which showed superior neuronal induction capacity compared to wild-type Ascl1. Furthermore, the combination of Ascl1SA6 with the survival factor Bcl2 further enhanced the efficiency of iN conversion. The study’s lineage tracing confirmed that the newly formed induced neurons were primarily from astrocytes. Interestingly, many of these induced neurons exhibited characteristics of fast-spiking parvalbumin-positive (PV+) interneurons.

In summary, the study demonstrates that Ascl1SA6, particularly in combination with Bcl2, could improve the efficiency and fidelity of glia-to-neuron reprogramming in vivo, with potential implications for therapies targeting neuronal loss and brain circuit restoration.

It should be kept in mind, however, that these cell type conversions a priori promote the appearance of cancers, that the new neurons are hardly useful, that the method used is gene therapy and therefore has very low efficacy and elevates cancer risks, that is is a report on experiences done in mice and they usually do not translate in humans and that it is not a question of conversion to neuronal stem cells which would be free of many of these problems.

Nevertheless, it's a step in the right direction.