Mediterranean diet and risk of multiple sclerosis: A prospective cohort study

Abstract

Background and Objectives:

Although adherence to the Mediterranean diet has been reported to be inversely associated with risk of neurodegenerative disease, it is uncertain if this dietary pattern also reduces multiple sclerosis (MS) risk.

Methods:

We analyzed data from 41,428 participants in the Swedish National March Cohort. Dietary intake was assessed at baseline in 1997 using a Food Frequency Questionnaire. The Mediterranean Diet Score was analyzed numerically (range: 0–9) and categorically (low, medium, high adherence). Participants were followed using national registries to identify MS cases. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models.

Results:

During a mean follow-up of 17.6 years, we identified 89 incident MS cases. Each one-point increase in the Mediterranean Diet Score was associated with a 14% lower MS risk (HR = 0.86, 95% CI: 0.75–0.99). When stratified by smoking, we found a 26% lower risk among non-smokers (HR = 0.74, 95% CI: 0.61–0.90), while no risk reduction was seen among smokers. In age-stratified analyses, inverse associations were observed in participants aged ⩽ 45 years (HR = 0.77, 95% CI: 0.64–0.93), but not in those aged >45 years.

Conclusions:

Adherence to the Mediterranean diet was inversely associated with MS risk, supporting its potential neuroprotective role.

Introduction

Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by myelin loss, inflammation, and neurodegeneration.¹ Common symptoms include visual impairment, sensorimotor dysfunction, fatigue, and cognitive deficits.¹ Onset is usually at ages 20–45 years, and there is a higher incidence in females.¹ Sweden has one of the highest global prevalence rates of MS (215 per 100,000).² Established and suspected causes of MS include genetic and environmental factors, such as Vitamin D deficiency,³ Epstein–Barr virus infection,⁴ smoking,⁵ obesity,⁵ and potentially also diet.⁶ Although the influence of diet remains under examination, the Mediterranean dietary pattern might be protective.^7,8 This dietary pattern, characterized by a high consumption of fruits, vegetables, olive oil, and omega-3 fatty acids, has previously been associated with a reduced risk of Alzheimer’s and Parkinson’s disease,^9,10 potentially due to its antioxidant and anti-inflammatory effects. Current evidence, although still limited in scope, suggests that individuals adhering to the Mediterranean diet may have a lower risk of developing MS, pointing to a potentially beneficial role for this dietary pattern.^7,8 To expand the limited knowledge, we examined the association between Mediterranean diet adherence and MS incidence in a large Swedish prospective cohort.

Methods

Study population

The Swedish National March Cohort was established in 1997 during a nationwide fundraising campaign by the Swedish Cancer Society. This 4-day event took place in nearly 3,600 cities and villages across Sweden. Participants were invited to complete a 36-page questionnaire on lifestyle and medical history, and 43,865 responses were collected.¹¹ Through the national registration numbers, the cohort was linked to the National Patient Register (inpatient data from 1987, outpatient diagnoses from 2001), the Cause of Death Register, and the Total Population Register (birth, immigration, and emigration data). The study was approved by the ethical review board in Stockholm (1997-205, 2017/796-31) and all participants provided informed consent. To identify MS diagnoses, we used the following International Classification of Diseases (ICD) codes: ICD-7: 345, ICD-8/9: 340, and ICD-10: G35, including both primary and secondary diagnoses.

We excluded participants with incorrect national registration numbers (n = 11), those who had died (n = 8), were under 18 years of age (n = 1,740), or had emigrated (n = 43) before start of follow-up. In addition, we excluded female participants with total energy intake outside the range of 500–3,500 kcal/day (n = 297), and male participants outside the range of 800–4,000 kcal/day (n = 307). These commonly applied cut-offs are used to exclude implausible energy intake.¹² Finally, we excluded those diagnosed with MS (n = 31) prior to the start of follow-up. The final analytical cohort included 41,428 participants.

Dietary assessment

Participants were followed from 1 October 1997, until the first MS diagnosis, death, emigration, or the end of follow-up on 31 December 2016, whichever occurred first. Baseline dietary intake was assessed using a validated 85-item semi-quantitative Food Frequency Questionnaire.¹³ Participants reported their average consumption for each food item and beverage during the previous year, with standard portion sizes provided. Response options ranged from 0 to 7 times/day, or as follows: 0; 1–3 times/month; 1–2, 3–4, 5–6 times/week; or 1, 2, 3+ times/day, depending on the item. Missing items were treated as no intake, consistent with the procedure used to calculate total energy intake. This approach ensured internal consistency in the dietary data while minimizing potential bias from differential non-response. Energy and nutrient intakes were derived using the Swedish National Food Composition Database.

We calculated average daily consumption, energy-adjusted the nutrients using the residual method, and assessed adherence to the Mediterranean diet using the Mediterranean Diet Score.¹⁴ The score ranged from 0 to 9, with 1 point assigned for consumption at or above the sex-specific median for each beneficial component (vegetables, fruits and nuts, legumes, grains, fish, and unsaturated-to-saturated fat ratio), and below the median for less favorable components (dairy and meat). For alcohol, 1 point was assigned for intake within specific ranges (5–25 g/day for females, 10–50 g/day for males); otherwise, 0 points were given. We defined categories of adherence as low (0–3 points, reference), medium (4–5 points), and high (6–9 points), in accordance with the original definition of the Mediterranean Diet Score,¹⁴ thus maintaining consistency with prior studies.

Statistical analyses

Baseline characteristics are presented as medians (interquartile ranges, IQR) for non-normally distributed continuous variables, means (standard deviations, SD) for normally distributed continuous variables, and frequencies (percentages, %) for categorical variables.

Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between Mediterranean diet adherence and MS risk, using age as the underlying timescale. The models were adjusted for several potential confounders: sex (female/male), smoking (non-smoker/smoker), BMI (<25.0/25.0–29.9/≥30.0 kg/m²), education level (⩽13/>13 years), leisure time physical activity (tertiles of metabolic energy turnover [MET] hours/week), energy intake (kcal/day), Vitamin D (µg/day), and Vitamin B12 (µg/day). We tested proportional hazards assumptions using Schoenfeld residuals. To examine possible effect modification, we fitted the cross-product interaction term between the dietary score and selected covariates (smoking, education level, and BMI) for each model, and tested statistical significance using the Likelihood Ratio (LR) test. Based on the results, we present stratified analysis by smoking for each model. Given the age-dependent nature of MS incidence, which typically occurs between 20 and 45 years of age,¹ we additionally fitted models stratified by baseline age category (⩽45/>45 years) to explore potential differences in associations across age groups. We also conducted a sensitivity analysis excluding MS cases diagnosed in the first two years of follow-up (n = 2) to avoid reverse causation.

Missing data were as follows: education 1.1%, smoking 2.2%, physical activity 3.9% and BMI 4.5%. Missing values were imputed using regression-based models. Logistic regression was applied for dichotomous variables (education, smoking), and ordinal logistic regression was applied for categorical variables (BMI, physical activity). The predictor variables were specified as follows: for education, predictors included sex, and age; for BMI, predictor were sex, age, total energy intake, and education; for smoking, predictor included sex, age, and education; and for physical activity, predictors were sex, age, education, total energy intake, and BMI. For each missing observation, predicted probabilities were generated, and the most likely category was assigned.

All statistical analyses were performed with Stata version 18.0 (Stata Corporation, Collage Station, TX, USA). p-values below 0.05 were considered statistically significant.

Results

Table 1 shows baseline characteristics according to Mediterranean Diet Score adherence categories. Among the 41,428 participants, the median Mediterranean Diet Score was 4 points (IQR, 3) and the mean age was 51.6 years (SD, 16.0), whereof 32.1% of the population was 45 years or younger. Most participants had a BMI below 25 kg/m² (61.6%), and females accounted for 64.5% of the cohort. Smoking status and dietary intake of Vitamin D and Vitamin B12 were evenly distributed across adherence levels. By contrast, participants with higher adherence to the Mediterranean diet tended to be older, more educated, and reported both a higher energy intake and higher levels of physical activity.

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