There are many unanswered questions about ALS:

• Why does it start at a specific point, for instance, the thenar muscle, leading to the split-hand phenotype?
• Why does it spread to other muscle areas?
• Why do only some muscle types get affected and not others? For example, only skeletal muscles are impacted.
• Why are only muscles and motor neurons affected when TDP-43 pathology appears in many other tissues?
• Are we certain that the century-old explanation —where motor neurons die first, followed by muscle death— is correct? Some scientists believe it might be the other way around (backward dying). Also, why should only motor neurons die? Muscle cells and neurons both originate from the same progenitor cells, share many characteristics, are extremely long, and consume much more energy than other cells. So, probably, they should become dysfunctional simultaneously.

A young scientist might risk her entire academic future if she attempts to answer these questions. The research and subsequent publication only take small, cautious steps without challenging the long-standing paradigms.

In a study published in Nature Communications, Kazuhide Asakawa and colleagues utilized single-cell imaging in transparent zebrafish to demonstrate that large spinal motor neurons are subject to a constant, intrinsic burden of protein and organelle degradation.

While not revolutionary, this study confirms or clarifies previous findings:

• Large spinal motor neurons have inherently high autophagy and proteasome activity, possibly as an adaptation to higher protein-folding stress.
• Loss of TDP-43 intensifies these degradation processes, reflecting cellular stress responses.
• Despite this, large SMNs are still most vulnerable in ALS, suggesting their intrinsic protein stress exceeds their degradation capacity.
• Enhancing autophagy may be neuroprotective, indicating that supporting degradation pathways could help preserve motor neuron function.

The study relies on zebrafish, a vertebrate model sharing many conserved neuronal and autophagic mechanisms with humans. However, there are species-specific differences. Humans and zebrafish are both in the phylum Chordata —they have spinal cords— but they are quite different otherwise.

Nevertheless, components of autophagy and UPS pathways are likely similar across both species. These intracellular systems are part of cellular quality control, maintaining cell health. Since these mechanisms consume energy, they are less efficient in already starving cells.

TDP-43 biology is nearly identical in zebrafish and humans. Moreover, motor neuron subtype heterogeneity (large vs. small motor neurons) and vulnerability differences are conserved. Human large motor neurons, like those in the spinal cord’s ventral horn, are more vulnerable in ALS, while oculomotor neurons remain relatively unaffected, mirroring zebrafish observations.

The core relationship (Large motor neurons → higher protein stress → increased autophagy and UPS activity → vulnerability when overwhelmed) likely applies in humans, too.

Potential differences between zebrafish and humans include development and aging. Zebrafish neurons develop rapidly, so chronic aging-related effects —like decades of protein damage accumulation— are not modeled. Human neurons are larger and possess more complex synaptic networks, so issues with autophagic capacity might have more complex outcomes.

In terms of clinical implications, these findings may translate into:

A. Diagnostic or prognostic insights:

• Autophagic or proteasomal markers could indicate early neuronal stress or degeneration in ALS.
• Imaging or CSF biomarkers of autophagy overactivation might someday identify vulnerable motor neurons before death.

B. Therapeutic implications:

• Boosting degradation systems could be protective. Since enhancing autophagy and UPS activity seems beneficial, mild pharmacological stimulation might help. But treating most cells in the body is difficult, and these systems consume a lot of energy, which diseased cells lack.
• Targeting upstream protein misfolding—because large neurons accumulate misfolded proteins—might be beneficial through agents that improve protein folding, like ER chaperones or chemical chaperones (e.g., 4-PBA or TUDCA). However, similar attempts have shown limited results.
• Restoring TDP-43 function may help, as its loss causes splicing errors and degradation stress. Gene therapy or RNA-based fixes could indirectly normalize autophagy. Multiple approaches have been attempted, but complex, unresolved issues may remain.

In conclusion, this study is interesting but not groundbreaking. We need therapies that rejuvenate unhealthy cells; we won’t cure such a devastating disease with small steps alone.

ApoE Isoforms, Glucose and Lipid Metabolism, and PPARα in Neurodegenerative Diseases

Apolipoprotein E (apoE) is essential for lipid transport and neuronal repair in the central nervous system. Of its three main forms—apoE2, apoE3, and apoE4—apoE3 is considered the “neutral” variant, supporting normal lipid balance and synaptic stability. In contrast, apoE4 is a major genetic risk factor for late-onset Alzheimer’s disease and several other neurodegenerative disorders.

Structural differences between apoE3 and apoE4 change how they bind lipids and trigger a cascade of metabolic and inflammatory disturbances that weaken neurons over time.

A key part of this vulnerability lies in energy metabolism. Neurons rely heavily on glucose, but in aging or disease, glucose uptake and utilization often decline. ApoE4 has been linked to reduced glucose transport and impaired mitochondrial efficiency, leading to energy shortages and oxidative stress.

The peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor regulating genes involved in fatty acid oxidation and lipid balance, plays a protective role in this context.

Together, apoE isoforms, glucose metabolism, lipid regulation, and PPARα signaling form a tightly linked metabolic network that shapes the progression of neurodegenerative diseases.

The New Study: Sortilin, ApoE, and Neuronal Energy Metabolism

A recent study explored how sortilin, a neuronal receptor, interacts with apoE3 and apoE4 to regulate how neurons use fatty acids for energy. Sortilin is known to participate in brain lipid metabolism and is thought to cooperate with apoE3 to maintain healthy neuronal lipid processing. The authors hypothesized that this partnership fails when sortilin is absent or when apoE4 replaces apoE3.

Experimental Models

Researchers examined four types of genetically modified mice:

• E3WT: human apoE3, sortilin present
• E3KO: human apoE3, sortilin knockout
• E4WT: human apoE4, sortilin present (but functionally impaired)
• E4KO: human apoE4, sortilin knockout

Key Findings

Only the E3WT neurons displayed high mitochondrial respiration (oxygen consumption). All other groups—E3KO, E4WT, and E4KO—showed lower respiration, even though their mitochondria were structurally normal. ➡️ Interpretation: Sortilin–apoE3 interaction is required for neurons to reach full mitochondrial energy capacity.

To identify which energy pathways were affected, the researchers blocked specific fuel routes:

UK5099 blocked glucose-derived pyruvate entry into mitochondria.

Etomoxir blocked long-chain fatty acid (LCFA) import via CPT1A.

They found that the defect was specific to long-chain fatty acid metabolism. Neurons could still metabolize medium- and short-chain fatty acids, which enter mitochondria independently of the carnitine transport system.

Human Cell Models

Using human induced pluripotent stem cells (iPSCs) carrying the same genetic combinations, the team generated astrocytes and neurons. All appeared normal structurally, but only E3WT neurons used both glucose and LCFAs for energy. The others (E3KO, E4WT, E4KO) relied exclusively on glucose, mirroring the mouse results.

When E4 neurons were cultured in medium from E3 astrocytes, their ability to use LCFAs returned. ➡️ Interpretation: ApoE4 disrupts sortilin’s metabolic function, but factors secreted by apoE3 astrocytes can restore it.

Neuronal Activity

Electrical recordings showed that under normal glucose conditions, E3WT and E3KO neurons fired similarly. When glucose was scarce, E3WT neurons maintained their activity by switching to fatty acid metabolism, while E3KO neurons did not. ➡️ Interpretation: Sortilin enables neurons to use fatty acids as an alternative fuel, a key mechanism for metabolic resilience during glucose shortage.

Pharmacological Rescue

Treatment with bezafibrate, a PPARα agonist, restored PPARα activity and increased expression of CPT1A in E3KO and E4 neurons. This also reinstated their sensitivity to etomoxir, indicating that fatty acid oxidation had resumed. ➡️ Interpretation: Activating PPARα can compensate for metabolic defects caused by apoE4 or loss of sortilin.

Conceptual Model

According to the authors, sortilin and apoE3 work together to import and metabolize lipids (especially polyunsaturated and long-chain fatty acids) and to activate PPARα-dependent genes for energy production and neuroprotection.

ApoE4, by binding sortilin abnormally, mimics a loss of sortilin function. Without this partnership, neurons lose their ability to oxidize long-chain fatty acids, leading to reduced mitochondrial respiration, lower levels of protective lipids, and weaker PPARα activation — ultimately impairing neuronal energy resilience.

Translational Outlook

These results are mechanistically insightful but not yet directly applicable to humans. The models reveal how apoE4 and sortilin influence neuronal metabolism, yet human validation remains essential before any clinical translation.

In neurodegenerative diseases, timing is critical. Because neurons in the adult brain do not divide and have very limited regenerative capacity, much of the damage is already irreversible once symptoms appear. Consequently, such studies are most valuable for developing preventive or early interventions, rather than curative therapies.

Current research, therefore, focuses on:

identifying individuals at risk (e.g., through APOE genotyping or early metabolic biomarkers),

and evaluating whether long-term activation of protective pathways — such as PPARα or mitochondrial support mechanisms — could maintain neuronal energy balance and delay disease onset.

Even if started later in life, treatments that restore lipid metabolism or support mitochondrial function might still preserve remaining neurons and slow disease progression.

A year ago, a new study drew attention because it was a "hopeful anomaly." It challenged the fatalistic narrative of ALS and provided a clear, new direction for this research field. The ALS therapeutic landscape has seen many failures. Most drugs only slow the disease slightly. For those living with ALS, this study was a concrete reason for hope.

The idea that the secrets to curing the disease might be found in rare individuals who mysteriously recover is a compelling story. It suggests that the biological processes of ALS aren't always one-way and that recovery, though rare, might be possible.

Now, some readers have published a response to this study.

It's behind a paywall, so I haven’t read it, but I can guess what it says. Additionally, a recent publication states: "variants in IGFBP7 were linked to rare "ALS reversals," but the existence of such cases remains controversial." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/

In the study published last year, researchers told that they gathered 22 documented reversal cases and validated them across the Target ALS database. This was a pilot case-control study at Duke ALS Clinic in Durham, North Carolina.

The investigators collected demographics, disease details, pedigree info, and saliva samples from ALS reversals. Whole-genome DNA was extracted and sequenced from these saliva samples. The genomes of ALS reversals were then compared to previous whole-genome sequences from a biorepository of de-identified samples of more typical ALS patients. https://clinicaltrials.gov/study/NCT03464903

The researcher has confirmed 34 of these "reversal" cases so far by reviewing medical records. These patients differ in demographics and disease features compared to typical ALS patients. One possible explanation is that these individuals are genetically different, granting them a form of disease "resistance".

However, it appears that cases of ALS reversal are primarily documented in this specialized clinic. This does not mean that such cases do not exist elsewhere, but the diagnosis of ALS and, therefore, of ALS reversal is complicated. For example, it differs between countries in Europe, the United States, and Asia. More importantly, diagnoses vary considerably among doctors.

The problem is that we don’t fully understand what ALS is. Most agree it’s a phenotype that can result from many different causes—some genetic, others from exposure to neurotoxins, physical injury, or other factors.

An example of these variations in practice: the clinical study manager accepted people with primary muscular atrophy (PMA) into his study but PMA is not ALS.

Another issue is how to define “reversal.” Here, reversal was defined as an improvement of at least 4 points on the ALS Functional Rating Scale, maintained for at least 6 months. The ALSFRS-R scale is known to be flawed; it can show improvement simply because of the use of new assistive devices. A 2016 paper co-authored by this researcher stated that most of these “plateaus” and “reversals” are temporary: "ALS plateaus and small reversals are common, especially over brief intervals." https://pubmed.ncbi.nlm.nih.gov/26658909/

The new publication also states: "It is not yet clear if extremely rare “ALS reversals” suffer from typical ALS, or rather from another, yet undescribed disease mimicking ALS diagnostic criteria." https://pmc.ncbi.nlm.nih.gov/articles/PMC12419016/

The last year's study didn't just describe the phenomenon; it identified a specific gene, IGFBP7. It linked reversals to a noncoding variant near IGFBP7, which influences IGF-1 receptor activity. Since IGF-1 has long been suspected of having neuroprotective effects (it has been tested in past ALS clinical trials), this genetic link feels biologically plausible. Yet, more than one hundred genes are associated with ALS, especially SOD1, FUS, and C9orf72 (~9% of cases). These genes aren’t directly related to IGF, making it hard to think that patients with mutations in those genes could still experience reversals.

The authors did openly acknowledge the study’s limitations, which likely sparked discussion:

• The "Reversal" group included only 22 participants. This is a major limitation, and the results must be confirmed with larger groups.
• The study shows a strong genetic link, but it doesn’t prove that the IGFBP7 variant causes the reversals. It seems Professor Bedlack is now exploring this path: https://pubmed.ncbi.nlm.nih.gov/40944442/

Biogen, Roche, Takeda, and Vertex Pharmaceuticals have exited the AAV capsid field. Meanwhile, Pfizer has completely abandoned all work in gene therapy.

This is very unfortunate for the neurodegenerative disease field, where many familial cases could, in theory, be cured with such technologies.

Many gene therapies have received regulatory approval. Most of these approaches use adeno-associated viruses (AAVs) and lentiviruses for gene delivery, in vivo and ex vivo, respectively.

The scientific foundation is solid (we understand how to design vectors and deliver genetic payloads), but industrialization faces many bottlenecks. Manufacturing costs per patient remain very high—hundreds of thousands of dollars.

Since gene therapies primarily target rare diseases, the patient populations are small. Companies cannot rely solely on scaling to lower costs. After the initial cohort is treated, the market shrinks dramatically.

While academia can demonstrate that gene therapies work on a small scale, industry needs to prove that these therapies are reliable, scalable, safe, and financially sustainable—much higher standards. This explains why many promising academic results lead to companies retreating when confronted with the challenges of large-scale production and commercialization.

Alternatives such as mRNA, antisense therapies (ASO), and protein drugs offer different balances of feasibility, durability, safety, and economic viability.

Huntington’s Disease and C9orf72 ALS: Shared Mechanisms and Therapeutic Hopes

Approximately 70,000 people have been diagnosed with Huntington’s disease (HD) in the U.S. and Europe, with hundreds of thousands more at risk of inheriting the condition. Despite the clear genetic cause of HD, there are currently no approved therapies that delay onset or slow progression.

Both Huntington's disease and C9orf72-linked ALS, while clinically distinct, share a common hallmark: long, abnormal repetitions of DNA bases. The success of antisense oligonucleotides (ASOs) in spinal muscular atrophy (SMA, SMN1 gene) in 2017, followed by gene therapy in 2019, gave researchers confidence to pursue similar strategies in HD and C9orf72 ALS. Progress in treating one of these repeat expansion diseases may provide hope for others.

1. Genetic Basis

1.1 Huntington’s disease (HD)

HD is caused by an expanded CAG trinucleotide repeat in the HTT gene. - Normal alleles: up to approximately 26 repeats - Pathogenic threshold: 36 or more repeats

CAG encodes glutamine, leading to a mutant protein with an expanded polyglutamine (polyQ) tract. This toxic protein disrupts neuronal function and accumulates throughout the body, contributing not only to neurodegeneration but also to systemic issues like muscle atrophy, cardiac problems, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.

1.2 C9orf72 ALS/FTD

C9orf72-related ALS and frontotemporal dementia (FTD) are caused by an expanded GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene. - Normal alleles: up to approximately 30 repeats - Pathogenic alleles: hundreds to thousands

The expansion causes disease through several mechanisms: - Reduced C9orf72 protein levels - Formation of toxic RNA foci - Production of abnormal dipeptide repeat proteins via repeat-associated non-ATG (RAN) translation

1.3 Other repeat expansion diseases

• Spinocerebellar ataxias (SCAs) – many caused by CAG expansions
• Fragile X syndrome – CGG expansion in FMR1
• Myotonic dystrophy – CTG expansion in DMPK

2. Therapeutic Approaches: Shared Strategies

2.1 Antisense oligonucleotides (ASOs)

ASOs aim to reduce toxic transcripts. - HD: ASOs targeting HTT mRNA have reached clinical trials (e.g., Roche/Ionis). - C9orf72 ALS: ASOs targeting repeat-containing transcripts are in early-stage trials.

2.2 Gene silencing/editing

The most advanced approach in HD is uniQure’s AMT-130 gene therapy: - Uses an AAV vector to deliver microRNAs designed to silence mutant HTT. - Administered through MRI-guided stereotactic neurosurgery directly into the striatum. - Clinical trials (U.S. and Europe) are ongoing, with promising early results showing up to 75% slowing in disease progression in high-dose patients over 36 months.

These approaches are not yet cures, but they show that disease modification is possible. Advances in vector design (AAVs, lipid nanoparticles) are directly transferable to other repeat expansion disorders.

2.3 Targeting RNA structures

Small molecules that bind abnormal RNA structures (hairpins, G-quadruplexes) are under development for C9orf72 ALS and myotonic dystrophy, with potential extension to CAG-repeat disorders like HD.

2.4 Modulating protein homeostasis

Strategies to boost autophagy, proteasome activity, or molecular chaperones could reduce toxic protein aggregates in both HD and C9orf72 ALS.

3. Translating Progress Across Diseases

Research tools—such as assays for RNA foci, protein aggregation, and repeat instability—are shared across laboratories working on different repeat expansion disorders. Breakthroughs in one disease can therefore be rapidly tested in others.

Delivery challenges are also common: therapies must reach neurons in the brain and spinal cord. Advances in intrathecal ASO delivery or viral vector engineering benefit all disorders in this family.

In summary: Huntington’s disease and C9orf72 ALS/FTD are distinct conditions, but they share a unifying principle: DNA repeat expansions that disrupt RNA and protein homeostasis. Therapeutic strategies—including antisense oligonucleotides, RNA-targeting drugs, and gene-editing technologies—are broadly applicable across these diseases. Progress in one field accelerates progress in others, offering shared hope for patients facing these devastating neurodegenerative disorders.

There are often many causes to a non-communicable disease, particularly neurodegenerative diseases are more a consequence of a systemic failure than caused by a specific phenomenon. The multitude of papers assigning a specific mechanism, each time different, to neurodegenerative diseases is just noise that drags down knowledge acquisition in these domains. Some authors have hinted at a phase transition to explain the misfolding of some proteins, but what triggers this phase transition was elusive.

In this post, I discuss a very general paper. https://elifesciences.org/reviewed-preprints/107962v1

In simple terms, the authors have discovered how our innate immune system launches an extremely powerful and rapid response to a tiny signal from a pathogen. This has implications for age-related diseases such as cancer or neurodegenerative diseases.

The Core Problem:

Our immune system needs to react decisively to a single bacterium or virus. This involves a massive cellular response like inflammation or programmed cell death (pyroptosis, apoptosis). However, the initial detection of a pathogen (a single molecule binding to a receptor) provides almost no energy to power this massive response.

The Discovery - "Metastable Supersaturation": The authors found that key immune signaling proteins, specifically those containing Death Fold Domains (DFDs) (like ASC, FADD, BCL10, MAVS, TRADD), exist in a unique physical state inside our cells called metastable supersaturation. These full-length adaptors retain nucleation barriers and are able to exist supersaturated in cells. In contrast, many receptors and effectors do not. This localizes the “spring-loaded” behaviour to central adaptors that link receptor sensing to downstream cell-fate decisions.

A subset of death-fold domains (DFDs) are intrinsically “supersaturable.” Using a systematic screen of 109 human DFDs with a distributed amphifluoric FRET (DAmFRET) assay in yeast, the authors show that a minority of DFDs switch from soluble → assembled in a discontinuous (nucleation-limited) manner — the hallmark of a large intrinsic nucleation barrier. These discontinuous DFDs can therefore exist metastably above their saturation concentration (Csat) while remaining soluble (i.e. supersaturated).

Imagine a supersaturated solution of sugar water. It holds far more dissolved sugar than it should be able to. It remains liquid until you drop in a single sugar crystal, which instantly triggers the entire solution to crystallize.

Similarly, these DFD proteins are present in concentrations far higher than their natural solubility limit. They are kept in a soluble, "primed" state only by a high energy barrier that prevents them from spontaneously assembling (like the sugar needing a seed crystal).

This state acts as a long-term energy reservoir. The cell expends energy to produce and maintain these high levels of protein, storing potential energy for a future immune response. The authors show that tissues/cell types with shorter lifespans (e.g., monocytes) tend to express higher adaptor supersaturation than long-lived cells (neurons), suggesting a trade-off between rapid innate responsiveness and longevity. They also find conservation of nucleation barriers in distant taxa (fish, sponges, bacteria), indicating the mechanism is ancient.

How It Works for Immunity: When a pathogen is detected (the initial signal), the pathogen-bound receptor acts as the "seed crystal." This seed triggers the instantaneous, explosive polymerization of the supersaturated adaptor proteins (like ASC or FADD). This amplification process consumes the stored energy from supersaturation, converting it into a massive biochemical signal that leads to inflammation or cell death.

This allows for a response that is immediate, decisive, and independent of the cell's current metabolic energy (which is often hijacked by pathogens).

The Trade-Off is Immunity vs. Longevity:

This mechanism comes with a cost. Maintaining a supersaturated, "primed" state means there's always a risk of a spontaneous, accidental activation (a stochastic nucleation event). This would lead to unwanted inflammation or cell death without any infection. The authors found evidence that this trade-off is real: short-lived immune cells (like monocytes) have much higher levels of supersaturation than long-lived cells (like neurons). This suggests a fundamental thermodynamic drive where the need for strong immunity may inherently limit a cell's lifespan.

The authors also showed this system is highly specific (DFDs from one pathway don't accidentally trigger others) and that the mechanism is evolutionarily ancient, found in everything from humans to sponges to bacteria, indicating its fundamental importance.

This groundbreaking discovery opens up entirely new avenues for treating a wide range of diseases by targeting this "supersaturation engine."

1. Autoinflammatory and Autoimmune Diseases Examples: Crohn's disease, rheumatoid arthritis, lupus, CAPS (Cryopyrin-Associated Periodic Syndromes), type 1 diabetes.

2. Infectious Diseases Examples: Sepsis, severe viral infections (e.g., COVID-19, flu).

3. Cancer Application: Some cancers evade the immune system by preventing immune cells from initiating cell death (apoptosis) in cancerous cells. They might do this by interfering with the supersaturation or nucleation of proteins like FADD.

4. Neurodegenerative Diseases Examples: Alzheimer's, Parkinson's, ALS.

Therapeutic Strategy: This research provides a deeper biophysical understanding of how proteins form aggregates. Insights into controlling nucleation barriers could lead to strategies for preventing the initial "seed" event that sparks the catastrophic aggregation of proteins like amyloid-beta or alpha-synuclein.

Risks, trade-offs, and practical challenges

Immunity vs longevity trade-off. The authors argue a thermodynamic tradeoff: lowering supersaturation protects cells from spontaneous death but reduces rapid responsiveness to pathogens. Therapies that blunt supersaturation may increase infection susceptibility.

Off-target/cross-seeding risk. Although the interactome is relatively specific, some cross-nucleation exists (e.g., PYD↔DED). Inhibiting one adaptor could have unintended effects on other pathways, or conversely, seeding one adaptor therapeutically could accidentally trigger another.

Drugging interfaces is hard. Filamentizing interfaces and nucleation kinetics are complex to target with small molecules; biologics or degradation approaches may be more tractable but have delivery challenges.

Temporal and quantitative control required. Because the system is switch-like, small quantitative changes in concentration or barrier height can produce large outcome differences; therapies need tight control to avoid tipping the balance toward immunodeficiency or hyperinflammation.

In conclusion This study moves beyond simply listing the components of immune pathways to explaining the fundamental physics and energy dynamics that make them work. By understanding that immunity is powered by a "loaded spring" mechanism of metastable supersaturation, we can now think about designing much smarter, more precise drugs that either stabilize this spring (for autoimmune diseases) or trigger it on command (for cancer).

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.