A recent study analyzed the plasma proteomes of over 2,000 participants to identify proteins and biological pathways associated with Alzheimer's disease and related disorders. https://www.nature.com/articles/s43587-025-00965-4

The widely held hypothesis among scientists is that sticky amyloid plaques in the brain are a hallmark of Alzheimer's disease. With the announcement that the initial work on this hypothesis was fraudulent, along with hundreds of unsuccessful clinical trials, a growing number of scientists suggest that other processes must be at play.

This new study suggests that factors outside the brain, such as processes in the blood and other organs, may contribute to the disease. The authors show that several biological processes, including those related to the extracellular matrix, proteostasis, the immune system, and metabolism, play an important role in Alzheimer's disease. This means that what happens in the rest of the body could influence the brain and how quickly Alzheimer's disease progresses. The study also highlights the strong influence of the APOE ε4 genotype and lipoprotein biology.

Extracellular matrix (ECM):

The ECM is closely linked to cerebral β-amyloid (Aβ) deposition and cognitive decline. Some ECM proteins, such as SMOC1 and SPON1, are elevated in both plasma and the brains of patients with Alzheimer’s, while others, like HTRA1, show opposite trends in the two compartments. Changes in the ECM could impact cognitive function independently of β-amyloid buildup and may be connected to vascular integrity loss.

ECM proteins are found throughout the body and provide structural and biochemical support to cells and tissues. They are produced by various cell types, with fibroblasts being the most common source in connective tissues. Other cells, such as cartilage chondrocytes and kidney mesangial cells, also produce ECM components.

Proteostasis:

This process, involving protein synthesis and clearance, is linked to both Aβ plaques and cognitive function. Increased protein synthesis correlates with better cognition, while enhanced protein degradation links to poorer cognitive performance. Further research is needed to understand how these processes interact in the brain and peripheral tissues.

The proteostasis network, which manages protein synthesis, folding, and degradation, operates across multiple cell compartments in all tissues. As a result, proteins involved in this process originate from organs like the liver, muscle, and adipose tissue.

Immune system:

Activation of the immune response in the blood is strongly associated with declines in cognitive function, even after accounting for Aβ plaques. This suggests that peripheral immune responses may contribute significantly to cognitive impairment.

Proteins involved in immune processes are primarily produced by immune cells like leukocytes (white blood cells) and by other cells in immune-related organs such as the bone marrow, spleen, and thymus.

Synaptic proteins:

The synaptic protein NPTXR was the only protein consistently associated with cognitive performance across all examined groups; higher NPTXR levels correlated with better cognition. However, the study found mixed associations for other neuronal proteins—some indicated healthy brain function, while others signaled neuronal damage.

Metabolism:

Unlike in the brain and cerebrospinal fluid, where increased metabolic proteins associate with cognitive decline, plasma proteins related to metabolism show the opposite trend. This inverse relationship suggests that these proteins may originate from peripheral non-neuronal sources or that their transport across the blood-brain barrier is tightly regulated.

Metabolic proteins participate in processes like glycolysis and energy production. They are produced by cells in tissues such as skeletal muscle, fat, and the liver, which is central to metabolic regulation.

Lipoproteins and APOE ε4:

Lipoprotein biology is closely linked to Aβ buildup in the brain and cognitive function. Lower plasma levels of lipoprotein proteins, including APOE, associate with higher brain Aβ levels. The study also confirms the widespread effects of the APOE ε4 genotype, influencing multiple pathways such as cell division and microtubule functions, potentially connecting Aβ and tau pathologies.

The liver mainly produces and regulates lipoproteins like VLDL and HDL, which are crucial for lipid transport in the bloodstream.

Conclusion:

The study showed that some biological pathways, including the extracellular matrix, are similar across blood, cerebrospinal fluid, and brain, but others, like metabolism and synaptic pathways, differ significantly. These findings emphasize the importance of studying proteins in multiple body compartments to fully understand their role in Alzheimer’s.

The researchers note several limitations, such as incomplete data on factors like medication use, the absence of long-term follow-up data, and limited information on neurofibrillary tangle (NFT) burden in most groups.

In summary, the study illustrates that the complex processes underlying Alzheimer's disease can be detected in blood plasma, identifying potential targets for future therapies and biomarkers. It also supports the idea of using blood tests as a less invasive, more accessible way to study and monitor the disease progression.

Most disease research involves inactivating or deleting biological entities like genes, proteins, or RNA. It's hard to imagine, in principle, how deleting an entity shaped by millions of years of evolution could benefit an organism. It's counterintuitive, yet sometimes it works due to a high level of redundancy in biological functions. What's more interesting, in my opinion, is research that aims to heal from disease by restoring health to a malfunctioning biological system.

Some scientists argue that neurodegenerative diseases are primarily age-related, so strategies to rejuvenate may help. Young plasma or bone marrow can rejuvenate aged animals, but these strategies have drawbacks.

A new study tested whether induced pluripotent stem cell–derived mononuclear phagocytes (iMPs) can offer similar regenerative effects in Alzheimer’s disease.

iPSCs are adult cells reprogrammed back into a stem-cell-like state. From iPSCs, researchers can generate various cell types, in this case, mononuclear phagocytes. It's a group that includes macrophages and microglia-like cells, which are key immune cells in both the body and the brain. The IMP treatment involves injecting these iPSC-derived phagocytes into middle-aged mice (11–12 months). They don’t cross the blood–brain barrier but instead release factors that influence the brain indirectly—for example, by modifying inflammation, supporting microglia, or affecting mossy cells.

What specific, observable results did the authors find? Regarding cognition and behavior, they observed that iMP-treated aging mice performed similarly to young mice in several tasks. In a test called "novel object location," iMPs fully reversed age-related deficits in some models. Most of us, as we age, would benefit from therapy in this area! The effects lasted up to 10 weeks of treatment. These findings were consistent across different mouse models, including immune-deficient NSG, wild-type BALB/c, and AD-prone 5xFAD. However, in Alzheimer’s model mice (5xFAD), iMPs improved memory tasks but did not reduce amyloid plaque load.

The authors found that some cell types benefited from the iMP therapy, but the effects weren’t due to overall neurogenesis. iMPs likely exert their effects via secreted factors. The authors also did not study how sex differences might influence the therapy’s effectiveness.

Overall, I find this article promising, but it has some shortcomings. Induced pluripotent stem cells (iPSCs) often retain an “epigenetic memory” of their tissue of origin. For example, skin-derived iPSCs might still carry subtle molecular traces that bias them toward skin-like fates. This raises questions about the mechanism of action; however, the reprogramming process may have reset many age-related cellular features.

As usual, more studies are needed, including investigations into gender differences. It’s clear that mice are not humans, so this article does not prove that this therapy might work in humans. Nonetheless, the principle behind this therapy appears promising, as it parallels the effects seen with young bone marrow transplants but does not require donor tissue. Additionally, iMPs can be generated autologously, reducing the risk of immune rejection.

A tool for ALS or FTD gene carriers.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases. A significant number of cases are linked to a hexanucleotide repeat expansion in the C9orf72 gene, making it the most common known genetic cause of both conditions.

Genetic counseling is essential in informing families about their risk, especially for those with a family history of the disease. Currently, children of C9orf72 mutation carriers are often told they have a 50% chance of inheriting the mutation. While technically correct based on Mendelian inheritance, this figure overlooks a critical factor: age-related penetrance.

Penetrance describes the likelihood that someone carrying a disease-causing gene will develop the disease. In cases of C9orf72-related ALS/FTD, penetrance increases with age, peaking around 58 years old. This means that simply knowing you carry the mutation does not give the full picture of your personal risk.

A new study addresses this limitation by developing a more precise method for calculating risk and providing an online tool for families.

The tool is available here: https://lbbe-shiny.univ-lyon1.fr/ftd-als/

While other research has focused on identifying genetic modifiers of disease risk, this study centers on a readily available and easily measurable factor: age.

The researchers used a Bayesian approach, a statistical method that updates probabilities with new evidence. In this case, the evidence includes the individual's age and family history. By integrating age-related penetrance data, the researchers created a model to estimate the probability of carrying the C9orf72 mutation and developing ALS or FTD within a specific timeframe. This approach is especially relevant for asymptomatic relatives, such as children, siblings, grandchildren, and niblings of mutation carriers.

Importance of this work:

This research is significant because it moves beyond the simplified 50% risk figure, offering a more personalized and accurate risk assessment for individuals at risk of C9orf72-related ALS/FTD. It helps inform decisions about genetic testing and could influence lifestyle choices or participation in clinical trials. As testing for C9orf72 becomes more common, the need for nuanced interpretation of results increases. The findings are highly relevant for families affected by ALS/FTD, providing a more realistic understanding of their individual risk profiles.

Originality:

The study offers original insights beyond the basic concept. Although age-related penetrance is a known idea, this research presents a concrete, mathematically sound method to incorporate it into risk calculations. The online simulator further enhances its practical use. The novelty is in applying a Bayesian framework to refine risk estimates in C9orf72-related ALS/FTD, providing a more sophisticated and personalized approach than traditional Mendelian risk assessments.

Conclusion:

This study makes a valuable contribution to ALS/FTD genetics. By offering a more detailed and personalized risk assessment, it can improve genetic counseling, aid in clinical trial recruitment, and deepen the understanding of the disease. The online simulator makes this complex information accessible to clinicians and families, increasing its practical impact.

I often complain that neurodegenerative literature is of low quality and has little usefulness. Here is an article that may be very different.

It's known that in some diseases, like cord spine injury, some motor neurons reverse to an immature state, and it is thought that this may have a protective effect. The authors reflected that inducing vulnerable mature motor neurons into an immature state might be beneficial, and they tested this hypothesis in-vitro and on mice. Two key transcription factors, ISL1 and LHX3, are the master regulators of the immature motor neuron gene expression program. These factors are naturally expressed during embryonic development but are typically turned off in mature neurons. Yet ISL1 and LHX3 are not the only proteins involved in the maturation process of motor neurons. 7,000 genes change their expression significantly throughout postnatal motor neuron maturation

The developmental stages from a stem cell to a mature motor neuron follow these steps: The process begins with neural stem cells in the developing spinal cord. These cells can develop into various types of neurons and glial cells. Under the influence of signaling molecules (like Sonic Hedgehog), the neural progenitors become motor neuron progenitors, which are now committed to the motor neuron lineage. These progenitor cells multiply. Then these progenitors stop dividing and differentiate into neuroblasts. At this stage, neuroblasts express key transcription factors like ISL1 and LHX3, which establish the fundamental identity of the motor neuron. The neuroblast begins to resemble more to a motor neuron: They extend a long axon out of the spinal cord towards their target muscle. The cell also starts to acquire its specific electrical properties. Then the neuron reaches its target muscle, forms a neuromuscular junction, and becomes a fully functional, electrically active cell. At this point, the early master regulators like ISL1 and LHX3 are largely downregulated, and the neuron enters its final, mature state. The authors designed a genetic therapy with an AAV virus vector to make mature neurons express two proteins that are only expressed in the immature state. The AAVs were specifically engineered to target motor neurons. In the study conducted on mice, the administration mode of the AAV viral vector was able to specifically infect the spinal motor neurons. Once inside the mature motor neurons, the AAV released the therapeutic genes. This caused the neurons to begin expressing ISL1 and LHX3 again By re-expressing ISL1 and LHX3, the researchers essentially re-activate that original "immature" genetic program. This causes the mature neuron to revert to a state that is genetically and functionally similar to its younger self, with renewed resilience and stress-coping abilities. They believe that turning on the immature genetic program essentially re-awakens the neuron's dormant ability to regrow and repair itself. While mature neurons in the central nervous system have very limited regenerative capacity, the authors are suggesting that ISL1 and LHX3 could be flipping a switch that bypasses this limitation.

This was not achieved in a linear process; On the contrary, the study tells of multiple steps to study what was achieved and to learn how to progress.

Their study focussed on SOD1 ALS, so they used a SOD1 mouse model to study dysregulation of SQSTM1 and how ISL1 and LHX3 expression influence it. Large, round aggregates of SQSTM1 (termed “round bodies”) are detectable in the cytoplasm of SOD1 ALS motor neurons At transduction efficiencies greater than ∼80%, SQSTM1 round bodies were almost completely abrogated, pointing to a cell-autonomous effect of ISL1 and LHX3 re-expression on SQSTM1 pathology.

The transfected mice survived longer than the control ones, and the effect is much more pronounced in females than in males. Yet that was not a cure, and the study was only on SOD1 ALS; there are multiple types of ALS, so we don't have a clear idea of the impact of this therapy on other genetic/familial and sporadic ALS. Also, the authors found that the expression of ISL1 and LHX3 lasts only two weeks, so there is little time for the therapy to work. It would be interesting to see a similar study on the other species of nervous cells. The authors also highlight that it is unknown if this therapy would be effective late stages of the disease when motor neuron degeneration is underway and non-cell-autonomous factors such as neuroinflammation contribute to clinical progression.

The number of mice was also very low (8 mice in the treatment group and 6 mice in the control group), to the point where it is not statistically significant.

But for me, this study has a potential that most other studies have not: They try hard to heal motor neurons, not simply to repress some of the hundreds of genes involved in ALS. Gene KO approaches are lazy; it's shooting in the dark. This study is a great step forward, even if therapy is probably one or two decades away.

There has been a recent surge in articles about the Integrated Stress Response (ISR) in neurodegenerative diseases. The hypothesis suggests that the ISR, a cellular mechanism for managing stress, becomes excessively prolonged in these conditions. Several refinements of this idea have been proposed, such as the notion that protein misfolding occurs because the endoplasmic reticulum cannot properly process proteins during ISR, leading to the accumulation of misfolded proteins in the cytoplasm, which causes various problems. For example, TDP-43 proteins fail to fold correctly and cannot be transported to the nucleus, where they play critical roles in DNA repair and virus defense.

In this blog, we have discussed this topic multiple times, including the Inflectis Sephin1/IFB-088 drug.

One such article about ISR is ALSUntangled #80, which discusses a drug called ISRIB (Integrated Stress Response Inhibitor).

Several ISR inhibitors have been identified, including Guanabenz, IFB-088, Salubrinal, and ISRIB. Some of these drugs, like Guanabenz, have significant side effects, making them less suitable for long-term and widespread use.

The outcomes of ALSUntangled are usually predictable; they tend to indicate that any drug they evaluate has limited interest for ALS. However, this time, it feels different, possibly because the two main authors, Javier Mascias Cadavid and Anna Mena Bravo, are from Spain.

They discuss ISRIB and how it was informally tested by 42 ALS patients in Spain, who reported subjective improvements and no side effects.

There are additional publications exploring whether ISRIB could be a promising treatment for ALS.

They say that ISR might be the culprit in a rare subtype of ALS, which is caused by a mutation in VAPB gene. The authors suggest that ISRIB might be useful. What should we consider about all this? Maybe we should ask why scientists are searching for new drugs instead of focusing on compounds of drugs that have already shown some effects. Perhaps everyone wants to get rich, so they avoid exploring drugs that can't be patented.

For example, nobody has research on the benefits of Meclofenoxate in ALS in the last 50 years! A recent publication suggests it might be useful in Parkinson's disease.

Can Exercise Mimic Dopamine Effects on Brain Signals in Parkinson’s Disease?

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement and is partly caused by the loss of dopamine-producing neurons deep in the brain. While medications that replenish dopamine can help control symptoms, researchers are increasingly asking: Can other interventions, like physical exercise, offer similar benefits?

A recent study investigated this by examining how regular, vigorous cycling influences brain activity in people with Parkinson’s. The findings don’t suggest that exercise replaces medication, but they do reveal something intriguing: exercise may partially imitate how dopamine alters the brain’s internal rhythms.

What kind of exercise was used in the study? The study focused on a specific type called dynamic cycling. It’s not just casual biking; it involves riding a motor-assisted stationary bicycle at a steady, fast pace, usually between 75 and 90 pedal rotations per minute. This style of cycling has been linked to improvements in motor symptoms like stiffness and slowness in people with Parkinson’s. But this study wasn’t about clinical symptoms; it was about electrical signals inside the brain and what they reveal. What did the researchers do? Nine individuals with Parkinson’s, all of whom had deep brain stimulation (DBS) implants, participated in up to 12 cycling sessions over a month. These implants allowed researchers to directly record brain activity from a small structure deep in the brain called the subthalamic nucleus (STN)—a region strongly involved in movement control and a common target in Parkinson’s treatments.

Before and after each exercise session, the researchers measured electrical signals from the brain, called local field potentials (LFPs). They analyzed two types of signals: - Periodic activity: rhythmic brain waves like beta waves. - Aperiodic activity: the background “noise” of brain signals, analyzed through a measure called the 1/f exponent.

What is the relationship between the hindbrain and subthalamic nucleus? Parkinson’s primarily involves the degeneration of dopamine-producing neurons in a midbrain area called the substantia nigra pars compacta (SNc). These neurons produce dopamine, a neurotransmitter vital for controlling movement. They project to other brain regions, notably the striatum. Loss of dopamine in the striatum causes the main motor symptoms of PD: tremors, slowness, stiffness, and balance issues.

The striatum uses dopamine to regulate two pathways: - The direct pathway (which promotes movement) - The indirect pathway (which inhibits movement)

The subthalamic nucleus (STN) is part of the indirect pathway and sends excitatory signals to the globus pallidus internus, which inhibits the thalamus, which in turn controls activity in the motor cortex.

In Parkinson’s loss of dopamine leads to overactivity of the indirect pathway, increasing activity in the STN. This overstimulates the GPi, which then excessively inhibits the thalamus. As a result, the thalamus cannot properly activate the motor cortex, causing slowed and reduced movement.

What did the researchers find? After a month of exercising, consistent changes appeared in brain signals from the dorsolateral part of the STN: - Power of rhythmic activity increased, indicating stronger brain waves. - The 1/f exponent also increased, suggesting the background neural activity became more organized and less noisy.

Interestingly, similar increases in the 1/f exponent occur when people take dopamine-based medication. This suggests that repeated exercise might induce brain states similar to those achieved with drug therapy, at least in certain regions.

However, not all areas of the STN showed changes. The ventral part of the STN remained unaffected, highlighting that the effects were both region-specific and gradual.

What does this mean? This study doesn’t claim that exercise cures Parkinson’s, nor does it prove symptom improvement directly linked to the brain changes observed. Instead, it shows that repeated, structured exercise can produce measurable alterations in brain electrical activity—some resembling the effects of dopamine therapy.

In other words, exercise might help “tune” the brain’s motor circuits to support better movement control, even if the mechanisms differ from medication. By directly measuring brain activity, this study provides early evidence that exercise can influence key brain areas involved in Parkinson’s.

It’s a reminder that improvements in Parkinson’s may come not only from drugs and surgery but also from consistent, targeted physical activity that stimulates the brain in new ways.

There are two ways to counteract the effects of dying neurons, and in both cases, physical activity plays a role. The first involves neighboring neurons forming new synapses to replace those that are lost. The second involves stem cells creating new neurons, but this process is limited by several factors: some neurons have complex structures connecting multiple brain areas, and in older individuals, the supply of stem cells is significantly decreased.

Although effective symptomatic therapies have been developed for Parkinson's disease (PD), treatments that modify the disease itself still do not exist.

Drug repurposing studies help identify potential disease-modifying treatments. One advantage of drug repurposing is that, since these drugs are already approved, their safety profiles are known. However, further industry investigation is unlikely because companies hesitate to invest in drugs whose intellectual property is owned by others. Generally, they might consider repurposing their own drugs, which extends patent life by claiming new uses. This can also lead to questionable combinations of approved drugs just to file a patent.

In an issue of Neurology, Tuominen et al. publish a nationwide observational cohort study in Norway aiming to identify new candidates for disease modification in Parkinson's disease. They analyzed Norwegian health registries from 2004 to 2020 to identify people with Parkinson's. The study included 14,289 individuals and found 23 drugs among a total of 219 drugs associated with a reduced eight-year mortality risk.

Nonetheless, this reduction remains minor, and there is no proof that these drugs caused improved survival. The authors note that, although their findings are exploratory and cannot be directly applied clinically yet, the identified drugs could be considered for future clinical trials. Indeed, funding should be sought for these future trials, and since it is almost always private investors who finance clinical trials, they would require more information before making any commitments.

However, this study has notable strengths compared to similar studies. Tracking specific disease milestones is crucial for evaluating the effects of potential disease-modifying treatments.

For nearly all of the 23 drugs discussed by Tuominen et al., the adjusted eight-year mortality curves for Parkinson's patients and healthy controls diverged and showed different slopes, suggesting these compounds may have a disease-modifying effect. This pattern has not been observed in other trials testing potential disease-modifying drugs.

When interpreting Tuominen et al.'s results, it is important to remember that correlation does not necessarily imply causation. A drug associated with lower mortality does not automatically prove that it caused the reduction.

On the one hand, the decreased mortality might simply reflect that healthier Parkinson's patients are more likely to be prescribed these drugs. For example, patients using tadalafil (for erectile dysfunction) may have better overall health and longer survival.

On the other hand, for the more difficult cases, some physicians may have focused solely on treating essential symptoms rather than prescribing a large number of medications.

Additionally, the number of patients in the "treatment" group is often small; for instance, only 170 patients used Levothyroxine sodium.

These days, major news stories about neurodegenerative diseases are rare. One headline in the trade press claims: "Harmless Virus Could Trigger Parkinson's Disease."

Most cases of Parkinson's disease are idiopathic, meaning the cause is unknown. However, several genetic mutations can also lead to this neurodegenerative disease, with approximately 20 to 25 percent of cases having a genetic cause. One of these mutations is in the gene encoding LRRK2, which can result in enzyme levels two to three times higher than normal. These mutations are more common in North African, Arab, Berber, Chinese, and Japanese populations.

There is some good news coming out on this topic, but I'll talk about another publication.

Every viral infection alters the genetic material of some (but not all) cells in our body. This is how a virus forces the host cell to rapidly produce thousands of copies of itself. In most cases, viruses are first abruptly eliminated by the innate immune system, killing the host cell. The adaptive immune system uses a more intelligent mechanism, producing specific antibodies that bind to the virus and often render it non-infectious. This process is called humoral immunity. The LRRK2 protein is highly expressed in immune system cells, particularly in response to bacterial pathogens like Salmonella.

The hypothesis that some neurodegenerative diseases are caused by viral infections is attractive because it could explain why these diseases appear with age and why they affect the nervous system, as many viruses tend to accumulate there with age.

In a new study, researchers analyzed brains provided by the Rush Alzheimer's Research Center (RADC) in Chicago, from 10 autopsied Parkinson's patients and 14 non-PD patients. They found traces of human pegylated virus (HPgV) in five Parkinson's brains, but none in healthy brains. Human pegylated virus is a virus related to hepatitis C. The virus has also been detected in the cerebrospinal fluid of Parkinson's disease patients, but not in the control group. However, the small sample size makes these results inconclusive.

Next, perhaps seeking stronger evidence, the researchers analyzed blood samples from 1,393 participants in the Parkinson's Progression Markers Initiative, a biological sample bank for Parkinson's disease research. Only about 1% of Parkinson's patients had HPgV in their blood, which is consistent with the infection rate in the general population.

Nevertheless, the scientists say that people infected with the virus exhibited different immune signals, particularly those with a mutation in the LRRK2 gene. They explained that since mutations in the LRRK2 gene are known to influence immune signaling, autophagy, and viral processing, these genotype-specific responses suggest that host genetics and viral interactions could influence immune responses to human pegivirus, promoting neuroinflammation and the development of Parkinson's disease.

At this point, I'm confused; they performed two experiments, one not significant and the other negative, but in the article, the scientists still suggest a possible link between Parkinson's disease and human pegivirus. However, the headline and abstract (which will likely be the only parts colleagues read) are much less definitive: they only suggest that human pegivirus alters the transcriptomic profiles of patients with Parkinson's disease.

This is a far cry from the headlines in the trade press: "Harmless virus might trigger Parkinson's disease."