When MS Genetic Risk Meets Working Memory: Evidence from Healthy Young Adults
Multiple sclerosis (MS) is traditionally understood as a chronic inflammatory and demyelinating disease of the central nervous system, characterized by neurological symptoms such as sensory disturbance, motor impairment, fatigue, and cognitive dysfunction. The article examines MS from a broader genetic and neurocognitive perspective, asking whether inherited susceptibility to MS may be detectable in healthy individuals before any clinical disease emerges. Rather than studying patients with diagnosed MS, the investigators analyzed healthy young adults and tested whether a higher polygenic risk score for MS was associated with working memory performance and white matter microstructure. This approach is scientifically important because it treats MS not only as a clinical disorder but also as a complex biological phenotype whose genetic influences may overlap with cognition and brain structure.
Study Design and Population
The study used data from 3,282 healthy young adults from Basel, Switzerland, divided into two independent subsamples: Basel 1, with 1,803 participants, and Basel 2, with 1,479 participants. Participants were between 18 and 35 years old and had no reported neurological or psychiatric disorders. Working memory was assessed using a verbal n-back task, particularly the 2-back condition, which requires participants to monitor a sequence of letters and identify when the current letter matches the one presented two positions earlier. This task is widely used in cognitive neuroscience because it captures the ability to maintain and update information over short time intervals. The study also included diffusion tensor imaging data from a subset of participants to evaluate fractional anisotropy, a neuroimaging measure related to white matter organization.
Polygenic Risk Scores as a Tool for Studying MS Susceptibility
A central methodological feature of the study was the use of polygenic risk scores, which summarize an individual’s inherited genetic liability for a disease by aggregating many genetic variants across the genome. The authors calculated MS polygenic risk scores using genome-wide association study data from the International Multiple Sclerosis Genetics Consortium. They also examined whether results changed when excluding the major histocompatibility complex region, a genomic region strongly implicated in immune-related MS risk. This distinction is important because MS genetics includes both immune-associated and broader polygenic components. By using multiple statistical thresholds for including genetic variants, the researchers evaluated whether the association with cognition was driven only by the strongest MS-linked variants or by a wider distribution of common variants.
Association Between MS Genetic Risk and Working Memory
The principal finding was that higher polygenic susceptibility to MS was significantly associated with poorer working memory performance among individuals in the lowest 10% of task performers. This association was observed for both 2-back accuracy and d-prime, a signal-detection measure that reflects the ability to distinguish target from non-target stimuli. Importantly, the association was not evident across the full performance distribution or among the highest-performing participants, suggesting that genetic susceptibility may be most detectable in individuals already showing relatively low working memory performance. The direction of effect was consistent across both Basel subsamples, strengthening confidence that the result was not merely sample-specific. The finding remained significant even when the major histocompatibility complex region was excluded, indicating that the association was not solely attributable to this highly influential immune-related genomic region.
Brain Imaging Findings and White Matter Microstructure
The authors also tested whether MS polygenic risk was associated with fractional anisotropy, a diffusion tensor imaging measure often interpreted as reflecting aspects of white matter integrity, fiber organization, or microstructural coherence. Contrary to some previous findings in children, the study did not identify a significant association between MS polygenic risk and brain-wide mean fractional anisotropy in healthy young adults. Nor did the authors find robust tract-specific associations after correction for multiple testing. They also applied a “pothole” method to identify localized white matter abnormalities, but this approach similarly did not reveal strong evidence that MS risk polygenic scores were associated with white matter alterations in this young adult cohort. These findings suggest that the relationship between MS genetic risk and white matter microstructure may be developmentally specific, potentially stronger in childhood than in adulthood.
MS Severity Genetics and Distinct Biological Pathways
In addition to genetic susceptibility to developing MS, the article examined polygenic risk related to MS severity. This distinction is scientifically meaningful because the genes that increase the likelihood of developing MS may not be identical to those that influence disease progression or severity. The authors found no significant association between MS severity polygenic risk and working memory performance. However, they reported a significant association between MS severity polygenic risk and brain-wide mean fractional anisotropy, along with suggestive associations involving additional diffusion imaging measurements. These results imply that genetic factors linked to MS severity may be more closely connected to central nervous system resilience or structural brain characteristics than to working memory performance in healthy individuals.
Scientific Significance and Future Directions
This study contributes to a more nuanced understanding of MS genetics by showing that polygenic susceptibility to MS may be associated with cognitive variation even in individuals without clinical disease. The findings suggest a possible genetic bridge between MS risk and working memory, particularly among low-performing young adults. However, the authors appropriately emphasize that replication is essential, especially in larger and more ancestrally diverse cohorts. The study population consisted primarily of individuals of European ancestry, limiting immediate generalizability. Future research may benefit from more demanding working memory tasks, longitudinal designs, and pathway-based polygenic analyses that could identify specific biological mechanisms linking MS susceptibility to cognition. Overall, the article advances the view that MS-related genetic risk may influence measurable neurocognitive traits before disease onset, while also highlighting that MS susceptibility and MS severity may involve partly distinct biological pathways.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Petrovska, J., Coynel, D., Freytag, V., de Quervain, D. F., & Papassotiropoulos, A. (2024). Polygenic susceptibility for multiple sclerosis is associated with working memory in low-performing young adults. Journal of the Neurological Sciences, 463, 123138.
