Why does multiple sclerosis (MS) strike unevenly? Decades of epidemiological research are helping us connect the dots – revealing patterns in geography, genetics, and environment that are reshaping our understanding of this complex condition.
“To conduct strong epidemiological studies, you need robust nationwide data sources.”, Professor Melinda Magyari, director of the Danish MS Registry and consultant neurologist at the Copenhagen University Hospital says, “In Denmark, the national MS registry has been collecting data on all MS patients over the last 75 years. This allows researchers to track incidence and prevalence, explore sex differences, the role of risk factors and comorbidities, socioeconomic impacts on patient, analyse treatment and diagnostic delays. For example, in the 1960s, the sex ratio was approximately 1:1, but today, worldwide incidence reports show a significantly higher female-to-male ratio of approximately 3:1. However, overall, both the incidence of MS and the female-to-male sex ratio appear to have stabilised since 2000. We continue to see an increase in MS prevalence, not only due to new diagnoses, but also because mortality rates are declining and people with MS are living longer.”
With 17,747 people living with multiple sclerosis, Denmark is among the countries with the highest MS prevalence, with approximately 300 cases per 100,000 inhabitants. A cohort study linked data from several nationwide sources, including the Danish MS Registry, Population Statistics, Cause of Death, and Historical Migration registries. All 28,145 individuals living with MS in Denmark from 1950 to 2023 were included [1]. The mean age of people with MS reached a peak of 54.2 years in 2023. In 1975, women made up 58.7% of the MS population, a proportion that rose to 68.5% in 2023. The incidence of MS remained relatively stable at around 3.5 cases per 100,000 people until 1975. By 2000, it had more than tripled, reaching 11.4 cases per 100,000. The incidence remained consistent through to 2022 [1].
The increase in incidence observed from 1950 to 2000 was likely driven by the growing number of neurologists and the wider availability of magnetic resonance imaging (MRI) in many countries [2]. Additionally, heightened public awareness, improved access to specialists and diagnostic services, and expanded treatment and care options may have further contributed to this trend [2]. Nevertheless, lifestyles changes and increased exposure to risk factors could also have played a role in the rising number of new MS cases [2].
Epidemiological risk factors for MS
Dr Eva Strijbis, from the Amsterdam University Medical Centre – UMC, tells us: “There are two types of risk factors: those that increase the likelihood of developing MS, and those that contribute to worsen the course of the disease. Importantly, these are not necessarily the same. Genetics are among the most important risk factors for developing MS, as certain set of genes significantly increase the likelihood of the disease.”
In the Project Y study, researchers from Amsterdam UMC showed that genetics significantly influence the lifetime risk of developing MS [3]. Nearly the entire population of individuals with MS born in 1966 in the Netherlands was included in the study [3]. Polygenic risk scores were calculated for the 285 participants with MS and 267 controls. Among those in the highest 10% risk group, the likelihood of developing MS rose to 1 in 92 for women and 1 in 293 for men. In contrast, among those in the lowest 30% genetic risk group, only 1 in 2,739 women and 1 in 7,900 men developed the disease [3].
Dr Strijbis continues, “These results suggest that polygenic risk scores could be used in the clinic to support a diagnosis or help prevent misdiagnosis. If a person has a very low polygenic risk score, it could serve as a red flag – prompting clinicians to consider alternative conditions that mimic MS.”
Environmental factors, such as a prior Epstein-Barr virus (EBV) infection, smoking, low sun exposure, low vitamin D, obesity during childhood or adolescence, are known to contribute to MS susceptibility [4].
Prof. Magyari tells us, “EBV virus is one of the main risk factors associated with the development of MS. We should also notice that we have been focusing on an underrepresented population. Historically, early studies on MS predominantly included white population. However, now we are studying diverse racial and ethnic groups, and many differences emerge.”
For example, in regions where MS prevalence is high, social determinants of health play a more crucial role for people from minority ethnic and racial backgrounds than for White individuals in the same regions (see also our Spotlight on the role of social determinants in MS) [5].
“MS shows a clear geographical variation, with higher incidence rates in regions farther from the equator.” Prof Magyari continues, “This has led to intriguing hypotheses about environmental and lifestyle-related risk factors. One particularly compelling observation is that migration before puberty can alter an individual’s risk: people who move from a high-incidence area to a low-incidence area before puberty tend to adopt the lower risk of their new location, and vice versa.”
First-generation immigrants arriving in Denmark before the age of 15 had a higher risk of developing MS than in their country of birth, but still lower than that of people born in Denmark [6]. On average, their risk level reached about 69% of the level seen in native Danes. In contrast, second-generation immigrants – who moved to Denmark after the age of 15 – maintained a risk level closer to that of their country of origin – approximately 45% of the risk faced by native Danes [6].
How inactivity may mimic MS progression
“Stop smoking. That is the most important thing.” Dr Strijbis says, “Other risk factors are associated with a worse prognosis, for instance low levels of vitamin D, but also comorbidities – especially cardiovascular disease, diabetes – and, in general, every condition that can worsen the performance or the functional well-being of the individual. In this regard, physical activity is fundamental because it can improve general strength, well-being, and daily functioning. It is also an important modulator of prognosis. While we do not yet have evidence that exercise changes the underlying biology of MS – such as reducing brain atrophy – we do know that physical performance improves with regular activity. Ongoing intervention studies using brain MRI and blood biomarkers aim to determine whether physical exercise can positively influence the biological course of MS. In the meantime, I always remind my patients that sitting for most of the day can lead to a gradual loss strength and endurance, making activities like climbing stairs more difficult and reducing overall stamina. This can even mimic MS progression, when in fact it is due to poor physical condition rather than disease worsening. I can share an example: one of my patients seemed to be entering a progressive phase of MS, but after starting a regular training and physiotherapy programme, she was eventually able to walk better than she had five years earlier.”
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Written by Stefania de Vito
Special thanks to Prof Melinda Magyari (Copenhagen University Hospital; Danish Multiple Sclerosis Registry) and to Dr Eva Strijbis (Amsterdam University Medical Centre, UMC) for their insights.
References
[1] Holm RP, Wandall-Holm MF, and Magyari M Brain 2025; 148(2): 626-634.
[2] Magyari M et al Brain Behav. 2021;11(1): e01921.
[3] Loonstra Floor C et al. Neurology 2024; 103(7): e209663.
[4] Waubant E et al. Ann. Clin. Transl. Neurol. 2019 6(9): 1905-1922.
[5] Amezcua L et al. Lancet Neurol. 2024; 23(10): 1050 – 1062
[6] Munk Nielsen N et al. Brain 2019; 142(6): 1587-1597.