**Background:** Ultra-processed foods (UPFs) are industrial formulations that are typically energy-dense and nutrient-poor. Higher UPF consumption has been linked to cardiovascular disease, depression, and all-cause mortality, but evidence regarding multiple sclerosis (MS) risk was lacking. This study investigated the association between UPF consumption and the likelihood of a first clinical diagnosis of central nervous system (CNS) demyelination (FCD), a common precursor to MS.
**Methods:** Data were drawn from the 2003–2006 Ausimmune Study, a case-control study conducted across four regions of Australia (Brisbane, Newcastle, Geelong, and Tasmania). Cases (n=282) were participants aged 18–59 years presenting with symptoms suggestive of inflammatory CNS demyelination, confirmed by a study neurologist. Controls (n=558) were recruited from the Australian Electoral Roll and matched to cases by age (±2 years), sex, and study region. After excluding participants with implausible energy intakes (<3000 or >21000 kJ/day), the analytic sample included 775 participants (267 cases, 508 controls). Dietary intake over the 12 months prior to interview was assessed using a validated 101-item food frequency questionnaire (FFQ). UPFs were identified according to category four of the NOVA classification system; 28 FFQ items were classified as UPFs and converted to servings/day using recommended serving sizes. The primary exposure was energy-adjusted servings/day of UPFs, calculated using the residual method. The outcome was FCD case status. Logistic regression with full propensity score matching was used, matching on: age, sex, study region, education, smoking history, body mass index (BMI), physical activity, history of infectious mononucleosis, dietary misreporting status, and total energy intake. The final model was bootstrapped with 500 repetitions and bias-corrected adjustment. The multivariable analysis included 734 participants (257 cases, 477 controls).
**Key Results:** Compared with controls, a higher percentage of cases had a history of smoking (61.3% vs. 52.5%; p=0.019) and a history of infectious mononucleosis (27.4% vs. 16.3%; p<0.0001). Median UPF consumption was 6.2 servings/day (IQR 4.3) among cases and 5.5 servings/day (IQR 4.4) among controls (p=0.889). No statistically significant interactions were found between UPF consumption and total energy intake, BMI, or physical activity. The overlap assumption for fully matched propensity scoring was met. Higher consumption of UPFs was statistically significantly associated with an increased likelihood of FCD (adjusted odds ratio = 1.08; 95% confidence interval = 1.00, 1.15; p = 0.039), representing an 8% increase in the likelihood of FCD per one energy-adjusted serving/day of UPFs.
**Clinical Implications:** This is the first study to report an association between UPF consumption and FCD or MS risk. The findings complement prior work from the Ausimmune Study showing that healthy dietary patterns (high in poultry, fish, eggs, vegetables, and legumes) were associated with lower FCD likelihood. Potential mechanisms include displacement of healthier whole foods by UPFs, promotion of gut dysbiosis and proinflammatory cytokine production leading to neuroinflammation, and increased exposure to synthetic chemicals such as phthalates. Study strengths include the use of a large, well-characterized early MS cohort with detailed covariate data. Limitations include the FFQ not being specifically designed to capture UPFs (missing items such as sugar-sweetened beverages and energy bars), grouping of diverse food types in some FFQ items, and limited generalizability due to a predominantly Caucasian population. The authors conclude that increased awareness about healthy eating and improved nutrition education may help individuals at risk of FCD or MS adopt healthier dietary patterns.