ALS researchers worldwide continue to build upon existing work and make new discoveries in the hopes of a world free of ALS. In the April 2025 Research Update, explore new insights into clinical trial data, new treatment targets, predicting disease onset and progression, and ALS genetics.
We have developed a Research Glossary that contains a list of scientific and medical terms and definitions relevant to ALS. This glossary was created to support knowledge-sharing by clarifying words that may be unfamiliar to our readers. Click here to download a copy.
For the initial regimens, primary endpoints assessed changes in disease progression (using the ALSFRS-R scale) and survival at 24 weeks. Secondary endpoints assessed changes in muscle strength and respiratory function. The master protocol has now changed the duration of the trial to 36 weeks, with other changes to endpoints.
Post-hoc analysis involves looking at the data after the study is completed for additional information and insights. These analyses should be interpreted with caution and are typically used to inform future studies.
Not a fat chance: can fatty acids help fight ALS and FTD?
Many cases of ALS and frontotemporal dementia (FTD) share a common genetic cause: a variant (mutation) in a gene called C9orf72 (C9). A group of researchers, including Dr. Ashling Giblin and Dr. Alexander Cammack, aimed to further investigate C9orf72 models and polyunsaturated fatty acids (PUFAs), since epidemiological studies appear to show an association with increased dietary consumption of PUFAs and decreased ALS risk, with longer survival after disease onset. Researchers know that these fats are important for brain health. However, in the context of ALS, it is difficult to confirm a direct relationship between the two, since epidemiological studies have other factors that may complicate interpretation (e.g. some people may exercise more or have better access to healthcare), lack a control group for comparisons, and often have measurement challenges and biases, especially with self-reported data. Therefore, more targeted research is needed for further insights into this correlation between PUFAs and ALS.
To explore the topic further, the group used fruit flies, iPS cells (human brain cells grown in the lab), and donated brain and spinal cord tissue for their experiments. In all models, they found that cells showed a consistent drop in certain fats and impaired lipid metabolism, especially for PUFAs. When the researchers fed these healthy fats to the fruit fly models affected by the C9orf72 genetic variant, the flies lived a little longer but not substantially. The exciting findings came when the researchers increased PUFAs levels directly in the neurons. By increasing the activity of enzymes that help produce PUFAs in the brain, they saw a significant increase in lifespan and better protection against cell damage, in both C9 and TDP-43 cells (another important ALS lab model).
This study suggests that a lack of healthy fats in the brain might play role in ALS and FTD – and that boosting these fats could have a protective role in ALS. However, the authors note that the delivery of PUFAs directly to the neurons is critical in this protective function, which is not the same as simply increasing dietary intake. More research is needed to assess how PUFA intake may influence disease progression in humans.
SUMO: wrestling with the stress of ALS
In the majority of ALS cases, it is common to see dysfunction of a protein called TDP-43, even in individuals without a variant in the TDP-43 gene. Because of that, scientists are working to better understand how TDP-43 is dysregulated and through what mechanisms it contributes to disease onset and progression.
ALS Canada-Brain Canada awardee Dr. Terry Suk, working in the lab of Dr. Maxime Rousseaux at University of Ottawa, investigated a process called SUMOylation that seems to be involved in this pathology. SUMOylation helps cells respond to stress by modifying protein function through tagging them with another small protein called SUMO.
By conducting experiments in mouse models of ALS, they speculated that SUMOylation may be an early line of defense to regulate TDP-43 in response to cell stress. When this regulation is disrupted, it can lead to its accumulation during stress recovery, potentially contributing to disease. The group also illustrated how SUMOylation might play an important role during aging, highlighting the importance of SUMOylation in maintaining healthy brain function. Interestingly, the mice studied also showed cognitive FTD-like presentation, but only in females, which could imply that TDP-43 might play an unknown role in sex specific behaviors.
This research suggests that SUMOylation acts as an early defense mechanism against cellular stress, and its disruption may increase the risk of disease. This work may someday lead to a new therapeutic pathway for ALS and TDP-43 pathology.
Predicting disease progression and survival in people living with ALS is challenging, but crucial for planning care and making treatment decisions. Recent studies highlight promising approaches for early diagnosis and biomarkers for tracking disease.
Brainstorming how to predict ALS
A new study led by ALS Canada-Brain Canada awardee Dr. Isabelle Lajoie, from McGill University, investigated how brain scans could potentially provide insights into individual progression. Dr. Lajoie and her team, working under the supervisor of Dr. Mahsa Dadar, analyzed MRI scans from 178 people living with ALS, comparing them to a control group. Data was taken from CALSNIC, a network of imaging researchers supported by the ALS Canada Research Program. Using advanced imaging techniques, they looked for patterns of brain shrinkage (atrophy) in both grey and white matter. These changes were then linked to how quickly the disease progressed and how long participants survived. They found that specific areas of the brain — specifically the corpus callosum, frontal lobe, and thalamus — showed shrinkage that was tied to a higher risk of death or need for long-term breathing support. Importantly, when researchers combined this brain imaging data with traditional clinical information, their ability to predict individual progression improved significantly.
Another recent study by Dr. Pedram Parnianpour, from University of British Columbia (under the supervision of Dr. Sanjay Kalra at the University of Alberta) provides further evidence that imaging can be a useful biomarker for tracking the disease. They found that texture analysis of brain MRIs, combined with something called the D50 model (a more nuanced way to measure how ALS develops over time than just assuming a linear decline) can reveal subtle changes linked to ALS progression and stage.
These studies show that brain imaging could become an important tool in ALS care, providing insights that go beyond the tracking of symptoms and helping individuals access the right interventions at the right time.
Learn more about CALSNIC, supported by an Arthur J. Hudson Translational Team Grant from ALS Canada and Brain Canada, made possible by generous donations from the Ice Bucket Challenge.
The sound of ALS detection
In a study by Dr. Andrew Hannaford, from Australia, researchers investigated if muscle ultrasounds could detect fasciculations (involuntary twitching) and signs of ALS, aiding its diagnosis. 94 individuals initially suspected of ALS were analyzed in the study, of which 45 were subsequently diagnosed. The group scanned different muscles to help clinicians distinguish ALS from similar conditions. People living with ALS often experience significantly more fasciculations, distinguishing ALS from other ALS-mimic diseases, such as myotonic dystrophy or hereditary neuropathy. In the end, they were able to detect ALS with nearly 90% accuracy, adding to the evidence that this type of test could be promising as an effective tool to aid in early diagnosis of the disease.
Blood vs Muscle: the race to an ALS biomarker
Neurofilament light chain (NfL), a protein released when nerve cells are damaged, is being increasingly investigated for its reliability as an ALS biomarker, with particular value in predicting disease progression. A recent study has provided further evidence on its use, comparing NfL levels with two other blood proteins to see which could best identify the disease and predict ALS course. The study, led by Dr. Etienne Mondesert, from France, investigated 140 people living with ALS. Researchers found that blood NfL levels were well detected using four different testing methods, which is helpful in demonstrating reliability of the levels reported across many different studies. The study also supports how NfL levels could potentially help in a panel of blood biomarkers that may someday accurately lead to ALS diagnosis, and it further solidifies the strong evidence for the use of NfL as a prognostic biomarker for use in research and in some aspects of care. In contrast, the other two proteins investigated, GFAP and pTau181, were far less reliable.
In addition, another study by Dr. Paola Fabbrizio, from Italy, investigated a protein called angiogenin, found in muscle tissue. Angiogenin helps muscles regenerate and build new blood vessels, offering a protective effect. Researchers discovered that higher levels of angiogenin were found in mouse models with slow progression, but not in fast progressors. In people living with ALS, higher levels were linked to milder disease. This study brings insights into whether angiogenin could become a biomarker to predict how fast ALS will progress, as well as explores a new therapeutic target that supports muscle regeneration. Previous studies also show that pathogenetic variants (mutations) in the angiogenin gene (ANG) have been linked to an increased risk of ALS, which supports further investigation into the area.
Gene mix: how multiple variants amplify ALS risk
While researchers are still working to understand the exact causes of ALS, it is known that some cases are caused by a genetic variant, and several genes have been identified that when altered, can contribute to disease.
A new study led by Dr. Alfredo Iacoangeli and collaborators takes a deeper look at what happens when multiple risky gene variants show up together – a concept known as oligogenicity. Using a large genetic database from Project MinE, the group analyzed over nine thousand people living with ALS and compared them to control individuals. They found that individuals who carried rare variants in multiple ALS-related genes had an increased risk of developing the disease, more so than those just carrying one. However, having multiple variants didn’t seem to affect how the disease progresses or when it starts.
This is the first large-scale study to confirm that about six percent of ALS cases may involve variants in multiple genes. The study could bring important implications for genetic testing and counselling, making the case that even if an individual already has a known ALS variant, it’s important to look for a complete genetic profile. Importantly, multiple variants may also someday influence personalized medicine and choosing the correct therapy for different individuals living with ALS.
Learn more about ALS Canada’s support to Project MinE .
Researchers supported: Dr. Sali Farhan & Dr. Guy Rouleau.
