ALS Could Be Predicted Years Before Symptoms, Proteomics Study Finds

Neurodegenerative diseases are typically defined by the presence of characteristic clinical phenotypes. However, it is increasingly recognized that early intervention could give people the best chance for meaningful positive effects. As a result, early detection and prevention are becoming major priorities.

Months to several years before amyotrophic lateral sclerosis (ALS) symptoms arise, levels of certain blood proteins may dramatically shift. By anticipating the arrival of symptoms, investigators could intervene with preventative therapies before the irreversible motor neuron damage that is characteristic of ALS sets in.

In this study, researchers analyzed data from the long-running, National Institutes of Health (NIH)-funded Pre-symptomatic Familial ALS (Pre-fALS) study, to identify a lineup of key proteins that may predict the emergence of clinically manifest ALS.

This work is published in Nature Medicine in the paper, “Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.”

“If someone carrying an ALS-associated genetic variant had asked me in the past when they would become symptomatic, I would have struggled to provide a reasonable estimate,” said Michael Benatar, MD, PhD, professor of neurology and public health sciences at the University of Miami. “These biomarkers give us a far better idea of the timing, allowing us to estimate the time to symptom onset with an average error of about 18 months. That’s something we can work with.”

For nearly 20 years, the Pre-fALS study has collected data and biological samples from people who are at significantly elevated genetic risk for ALS but have not yet progressed, or phenoconverted, to the disease. While this cohort is unique, permitting the examination of presymptomatic ALS, recent studies suggest that findings from Pre-fALS are likely relevant to the broader population.

In 2017, an analysis of ten Pre-fALS participants who had developed symptoms showed that neurofilament light chain (NfL), a structural protein in neurons, spiked in their blood in the months preceding ALS phenoconversion. As more study participants have begun showing symptoms or signs of disease, new opportunities to search for other pre-symptomatic ALS biomarkers have emerged.

Now, using Olink Explore, investigators report a high-throughput, proteomic study on 516 serially collected plasma samples from 137 study participants; 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls.

The team identified 92 whose levels differed in people before they eventually showed symptoms. Using machine-learning techniques, the authors tested how various combinations of proteins could predict future risk of phenoconversion. Characterizing the longitudinal trajectory of these proteins, they identified a core panel of 19 proteins (including NfL) which, collectively, the authors note, predicted phenoconversion over the 0.5-year to 5-year time horizons and yielded estimates of time to phenoconversion with a mean absolute error of 1.6 years.

They also produced similar results using data from the UK Biobank, which, despite some limitations, is more representative of the general population than the genetically predisposed cohort of Pre-fALS.

“With preventative gene-targeting treatments now becoming available, there is a particularly urgent need for reliable biofluid-based signatures that indicate near-term onset in individuals that carry ALS risk genes,” said Amy Bany Adams, PhD, acting director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

Tofersen, a drug approved for symptomatic ALS, is currently being evaluated as a preventative therapeutic in pre-symptomatic ALS through ATLAS, a clinical trial designed by Benatar in partnership with the company Biogen. ATLAS will test whether starting treatment shortly before symptoms appear could avert or delay the onset of ALS.

“This is all possible because of the members of the carrier community who believe in our mission of preventing ALS and have supported and participated in our research. It has been one of my life’s greatest privileges to give something back,” Benatar said.

The post ALS Could Be Predicted Years Before Symptoms, Proteomics Study Finds appeared first on GEN – Genetic Engineering and Biotechnology News.

Mobility Patterns and Mental Health During the COVID-19 Pandemic: Longitudinal Observational Study Using Smartphone Mobility Data

<strong>Background:</strong> The COVID-19 pandemic disrupted mobility globally, but its mental health implications remain difficult to characterize because most studies relied on lockdown status, population-level mobility indicators, or self-reported mobility. These approaches may miss individual differences in actual movement patterns and cannot fully examine bidirectional relationships between mobility and mental health. Individual-level smartphone geolocation data may provide a more objective and temporally aligned measure of mobility during periods of societal disruption. <strong>Objective:</strong> This study aimed to use individual-level Google location history (GLH) data and population-level Google community mobility reports (GCMRs) to examine concurrent and longitudinal relationships between pandemic-era mobility patterns and mental health symptoms in Hong Kong. <strong>Methods:</strong> This study analyzed data from the CU-COVID19 cohort study, an online longitudinal survey study of the psychological impact of the pandemic in Hong Kong. Mental health symptoms over the previous 14 days were assessed at baseline, 6 months, and 12 months using the 9-item Patient Health Questionnaire, the 7-item Generalized Anxiety Disorder scale, and the 4-item PTSD Checklist for DSM-5. Participants provided retrospective GLH data reflecting their mobility during the corresponding 14-day survey periods. The analytic sample included 145 participants with baseline GLH data, of whom 110 had 6-month follow-up data and 49 had data available at all 3 assessment waves. GLH data were used to derive mobility factors representing journey diversity, immobility, and remoteness. Population-level mobility during the same 14-day periods was measured using Hong Kong GCMR residential stay data. Concurrent mediation models examined whether individual mobility mediated associations between population-level residential stay and mental health symptoms. Longitudinal models examined bidirectional associations between changes in individual mobility and mental health across 6-month intervals. <strong>Results:</strong> Population-level residential stay was not directly associated with mental health. In concurrent mediation models, higher population-level residential stay was associated with lower individual journey diversity (β=–0.36; <i>P</i>&lt;.001), and lower journey diversity was associated with higher depression (β=–0.29; <i>P</i>=.02) and posttraumatic stress disorder (PTSD) (β=–0.35; <i>P</i>=.002). Bootstrapped indirect effects suggested mediation through journey diversity for depressive symptoms (β=0.11, 95% CI 0.02-0.25) and PTSD symptoms (β=0.13, 95% CI 0.05-0.27), although the depression-related indirect effect became less robust after adjustment for local and individual COVID-19 infection indicators. Longitudinally, higher baseline depressive symptoms predicted subsequent reductions in journey diversity (β=–0.15; <i>P</i>=.02), and reductions in journey diversity predicted higher subsequent depressive symptoms (β=–0.43; <i>P</i>=.008). <strong>Conclusions:</strong> Individual-level mobility patterns, particularly lower journey diversity, showed more consistent associations with mental health symptoms than population-level residential stay. Findings suggest bidirectional relationships between mobility and mental health and demonstrate the potential of smartphone geolocation data for digital phenotyping. However, the modest and self-selected sample, limited GCMR availability, and observational design require cautious interpretation.

Daily Multivitamin May Help Older Adults Maintain Cardiovascular Function

A daily multivitamin-mineral supplement modestly improved cardiovascular-related functional health in older adults over three years, according to a secondary analysis of the large COSMOS randomized clinical trial. The findings suggest that routine multivitamin use may help preserve day-to-day physical functioning as people age, particularly among those with certain preexisting cardiovascular conditions.

The research was presented July 27 at NUTRITION 2026, the annual meeting of the American Society for Nutrition.

The findings add to a growing body of evidence from the COSMOS trial suggesting that daily multivitamin supplementation may support healthy aging. Previous analyses reported modest improvements in cognitive function and slower biological aging, although multivitamins have not been shown to reduce major cardiovascular events.

The analysis included 16,027 participants from the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), a randomized, double-blind, placebo-controlled trial that enrolled 21,442 U.S. adults without major cardiovascular disease at baseline. Men were at least 60 years old, and women were at least 65 years old when they entered the study.

Investigators evaluated participants’ responses to the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated patient-reported measure of cardiovascular health status. The questionnaire assesses physical function, symptom burden, and an overall clinical summary score reflecting the combined impact of both.

Participants assigned to receive a daily multivitamin experienced small but statistically significant improvements in symptom burden compared with those receiving placebo. While the supplements did not significantly improve physical ability scores overall, they produced a modest improvement in the overall clinical summary score.

“The results provide new evidence that a daily multivitamin modestly improved cardiovascular-related functional health, with more pronounced benefits in those with existing carotid stenosis,” the investigators concluded.

The largest benefits were seen in participants with carotid stenosis, a narrowing of the carotid arteries that increases the risk of stroke. Among the 122 participants with the condition, multivitamin supplementation produced clinically meaningful improvements in cardiovascular functional health scores, suggesting this subgroup may derive greater benefit than the broader study population.

The researchers noted that maintaining cardiovascular functional health has practical implications for older adults. Improvements in symptom burden may translate into greater ease performing everyday activities such as dressing, bathing, walking, climbing stairs, and completing household chores. Reduced fatigue, shortness of breath, and swelling could also help older adults remain active and independent.

The trial also evaluated cocoa extract supplementation, but it did not improve cardiovascular functional health in the study population overall. However, a subgroup analysis suggested cocoa extract helped preserve symptom burden scores among participants with heart failure, indicating that additional studies may be warranted in patients with established cardiovascular disease.

Unlike many nutrition studies that focus on disease prevention, this analysis examined how supplementation affected participants’ daily functioning and quality of life.

The investigators cautioned that the observed improvements with multivitamin use were modest and should not be viewed as a replacement for established healthy lifestyle measures such as maintaining a nutritious diet and engaging in regular physical activity.

Because this was a secondary analysis, the findings should be considered hypothesis-generating. The authors said future targeted clinical trials are needed to determine whether specific groups of older adults—particularly those with carotid stenosis or other cardiovascular conditions—may experience greater functional benefits from daily multivitamin supplementation.

The post Daily Multivitamin May Help Older Adults Maintain Cardiovascular Function appeared first on Inside Precision Medicine.

MapLight’s Schizophrenia Candidate Has Mixed Results at Phase II

MapLight Therapeutics announced this week that its candidate drug for treatment of schizophrenia had achieved its primary endpoint in a Phase II trial, but only at the twice daily dose tested in the trial.

As reported by the California-based company, while participants of the trial who were given the candidate drug, ML-007C-MA, once a day did show some signs of improvement it was not statistically significant.

ML-007C-MA is a combined muscarinic agonist (betovumeline) and peripherally acting anticholinergic (fesoterodine). It acts by turning on two receptors in the brain, M1 and M4.

M1 is the main receptor the drug is trying to stimulate in the brain cortex and hippocampus, where it is linked to cognition, attention, and possibly some aspects of psychosis. Turning on M4 also helps by acting like a brake on the overactive signaling that contributes to hallucinations and delusions. Betovumeline activates both M1 and M4 centrally, while fesoterodine is there mainly to block unwanted side effects outside the brain, like gastrointestinal issues.

In this study, MapLight randomized 307 adults with an acute exacerbation of schizophrenia to treatment with either a twice daily or once daily treatment with ML-007C-MA or placebo for five weeks.

At five weeks, patients given the twice daily dose had a statistically significant and clinically meaningful reduction in Positive and Negative Syndrome Scale (PANSS) total score of 4.5 points compared to placebo. Cognitive scores were also better in the twice daily group versus placebo.

While this result is positive overall, the non-statistically significant result for the once daily dose proved unpopular with investors and company shares on the Nasdaq fell 40% after the announcement.

In September 2024, Cobenfy, the first muscarinic M1/M4 agonist drug for treatment of schizophrenia was approved by the FDA. Now owned by BMS, Cobenfy will be the main competitor for ML-007C-MA if approved.

Cobenfy was groundbreaking because it was the first new mechanism of action for schizophrenia in decades, moving beyond dopamine blockade to a muscarinic approach and targeting both hallucinations and delusions as well as the more cognitive aspects of the disease, which are not well treated with other drugs.

Despite the approval of Cobenfy, a number of other competitors developing treatments for schizophrenia have failed in recent years. Whether MapLight can succeed at Phase III with ML-007C-MA—which is also being tested as a treatment for psychosis linked to Alzheimer’s disease—and compete with Cobenfy, remains to be seen.

The post MapLight’s Schizophrenia Candidate Has Mixed Results at Phase II appeared first on Inside Precision Medicine.

Large Genomic Atlas Maps How Pregnancy Shapes Maternal Biology

Pregnancy is often described clinically through its complications: gestational diabetes, hypertensive disorders, fetal growth restriction, preterm birth. But beneath those diagnoses is a moving biological system. Maternal metabolism, immunity, hematology and endocrine function are continuously adapting to fetal development, and standard reference ranges only capture part of that complexity.

A new Nature Genetics study puts genomics into that timeline. Using noninvasive prenatal testing data from up to 121,579 unrelated Chinese pregnancies, researchers mapped genetic associations across 111 prenatal and postnatal phenotypes, from blood counts and glucose markers to liver enzymes, thyroid function, serum screening scores, non-invasive prenatal testing (NIPT) risk scores, gestational disorders and birth outcomes. The result is what the authors call “a dynamic genetic atlas of human gestation.”

Turning routine NIPT into a genomic resource

The scale of the study is notable because it uses data already generated in routine care. NIPT produces low-depth sequencing data from maternal plasma, primarily to screen for fetal aneuploidy. Here, the team used those data to infer maternal genotypes and link them to longitudinal clinical measurements from two hospitals in Shenzhen.

Across the 111 gestational phenotypes, the researchers identified 4,688 independent genome-wide significant signals, including 1,703 associations not previously reported for the same or related traits. Many new signals appeared in areas that have been relatively underexplored, including maternal serum screening and NIPT-based trisomy risk scores.

Prenatal screening outputs are usually interpreted as biochemical or fetal-risk measures. This study suggests that maternal genetic background also contributes to variation in some of those scores, which could eventually matter for calibration of risk models.

Pregnancy is not a static genetic context

The more interesting message is not just that gestational traits are heritable. It is that some genetic effects appear to be specific to pregnancy.

By comparing gestational results with nonpregnant female datasets from BioBank Japan and the Taiwan Biobank, the researchers found that 7.8% of high-confidence signals across 30 phenotypes were gestation-specific. These loci were enriched in pathways linked to fetal development, pregnancy maintenance, growth regulation and hormonal adaptation, with genes such as IGF1, ESR1, and PPARG emerging as network hubs.

The study also captured time-varying genetic effects. For 24 complete blood count traits measured repeatedly across pregnancy and postpartum, 18.7% of associated variants showed genotype-by-gestational-timing interactions. In other words, the effect of a variant could strengthen, weaken or shift depending on whether a patient was in the first trimester, late gestation, delivery or postpartum period.

For precision medicine, that is the key point. Pregnancy is not simply a confounder in female health studies; it is a distinct biological state with its own genetic architecture.

Pregnancy as an early health signal

The authors also connected gestational phenotypes with 80 later-life diseases and medication-use traits in BioBank Japan. Genetic correlation and Mendelian randomization analyses linked gestational glycemic traits with diabetes risk, and gestational adiposity, lipids and blood pressure with cardiovascular outcomes.

These results support the idea of pregnancy as an early-life cardiometabolic stress test. However, the interpretation needs care. When the researchers adjusted for related phenotypes from the Taiwan Biobank, many associations were attenuated, suggesting that pregnancy may reveal pre-existing genetic susceptibility rather than directly causing later disease.

The study is therefore less about predicting individual outcomes today than building the architecture for doing so tomorrow. Its limitations are important: the cohort was Chinese, several rarer complications such as preeclampsia were underpowered, and fetal-versus-maternal genetic contributions still need to be separated.

Even so, the direction is clear. Routine prenatal data may become more than a snapshot of pregnancy status. Combined with genomics, it could help define who is adapting normally, who is deviating early, and who may need closer follow-up long after delivery.

The post Large Genomic Atlas Maps How Pregnancy Shapes Maternal Biology appeared first on Inside Precision Medicine.

STAT+: Pharma’s drug spending deflection

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Hello! Wanna drop some cars in an open pasture? The internet does it again. Drop some tips and feedback here: bob.herman@statnews.com.

PhRMA doesn’t want you to look at drug spending

Lobbying groups frequently send news releases and talking points to journalists as a way to influence reporting. Right now, the pharmaceutical industry’s primary lobbying shop, PhRMA, wants everyone to ignore the clear-cut rise in prescription drug spending. 

Continue to STAT+ to read the full story…

<![CDATA[Phase 2 ZEPHYR finds oral betovumeline combo reduces PANSS and improves cognition in acute schizophrenia, with generally mild side effects.]]>

OpenAI called the Hugging Face attack unprecedented. But we’ve been here before. 

This story originally appeared in The Algorithm, our weekly newsletter on AI. To get stories like this in your inbox first, sign up here.

Reading OpenAI’s account last week of how some of its models broke their containment and hacked into the computer systems of Hugging Face, another AI company, was the first time I got genuine chills about what large language models are now able to do. But this is a case of human hubris, not rogue AI.

I am not an alarmist. In fact, I have been pushing back against AI scare stories for years. Even so, this incident crossed a line. I think it’s the clearest illustration yet of how the people building and testing this technology do not fully understand what they’re doing. OpenAI could—and should—have seen this coming.

Here’s what happened, at least according to the two companies involved. A couple of weeks ago, OpenAI started testing the hacking abilities of some of its new models, including GPT‑5.6 Sol (released in June) and what OpenAI describes as “an even more capable pre-release model.”

OpenAI pitted its models against a benchmark called ExploitGym, released in May, which challenges LLMs to find ways to exploit real-world vulnerabilities found in commonly used software.

To see what they could do, the researchers removed most of their cybersecurity guardrails. Then they ran the models inside a sandbox that was cut off from the internet except for one link to a third-party piece of software that acted as a proxy to the outside world, and let them install code that they needed to beat ExploitGym.

On July 9, according to reporting by Reuters, OpenAI’s models started trying to break through the proxy. They found an unknown bug in the proxy’s software and used it to access the internet. From there, they broke into Hugging Face’s computer systems on July 11, apparently looking for data sets and solutions that would help them complete their task. Hugging Face announced the hack on July 16. 

OpenAI did not realize (or at least did not reveal) that its models were involved until July 21, around 10 days after they broke containment and a week after Hugging Face had shut down the attack and alerted the FBI.

In a statement given to MIT Technology Review, OpenAI says: “We are conducting a thorough review along with external advisors and with oversight from our Safety and Security Committee. Once the review is complete, we will publish a technical report of our learnings for everyone.” The firm also confirmed that its researchers were properly using existing safety guidelines and procedures at the time.

Wake-up call

OpenAI has said the event was unprecedented—and in many ways it was. This was the first time outside of a simulation that LLMs escaped what was thought to be a secure sandbox, accessed the open internet, and attacked an unrelated organization. It’s a wake-up call that shows just how good the latest LLMs are at finding and exploiting vulnerabilities in real-world software with little or no human guidance.

And yet at the same time, what OpenAI’s models did is something this technology has done for years. Give a model a goal and it will very often achieve that goal in unexpected ways, finding loopholes that look like cheats. OpenAI itself has studied this behavior.

A decade ago, it shared results of an experiment in which a model was tasked with beating a video game called CoastRunners. Human players take it for granted that the way to do this is by racing a boat through a series of flags to the finish line, racking up points for each flag you hit. OpenAI’s model figured out that you could get a high score by spinning in a circle and hitting the same three flags over and over again. There have been dozens of similar examples from researchers since. AI will always find a way.

“Despite repeatedly catching on fire, crashing into other boats, and going the wrong way on the track, our agent manages to achieve a higher score using this strategy than is possible by completing the course in the normal way,” OpenAI wrote in a blog post about the CoastRunners experiment in 2016. “While harmless and amusing in the context of a video game, this kind of behavior points to a more general issue … it is often difficult or infeasible to capture exactly what we want an agent to do.”

I couldn’t help thinking about CoastRunners when I read OpenAI’s blog post about the Hugging Face attack: “All evidence suggests that the models were hyperfocused on finding a solution for ExploitGym, going to extreme lengths to achieve a rather narrow testing goal … After gaining internet access, the models inferred that Hugging Face potentially hosted models, datasets and solutions for ExploitGym. Knowing this, the model searched for and successfully found ways to gain access to secret information that it could use to cheat the evaluation.”

Last week’s news was not about rogue AI, despite the headlines. It was about models achieving the goal they had been given: Find ways to exploit vulnerabilities in software. The fact that those models then behaved in a way OpenAI had not anticipated isn’t surprising. But it is worrying.

Back in 2016, OpenAI had this to say about its CoastRunners bot: “More broadly it contravenes the basic engineering principle that systems should be reliable and predictable.” A decade on, those basic engineering principles are still AWOL.  

<![CDATA[New analysis shows COMP360 psilocybin sessions for PTSD stay mostly silent, with nondirective support boosting safety and autonomy.]]>
<![CDATA[After TBI, soluble TNF sparks Alzheimer-like damage; XPro1595 blocks it in mice, preserving memory and reducing pain—hinting prevention.]]>