Dietary Patterns and Lifestyle Factors as Determinants of Body Mass Index and Body Composition in Individuals with Down Syndrome—A Study Across Three Clinical Sites

<b>Background/Objectives:</b> It is often reported in the literature that the prevalence of obesity is high in individuals with Down Syndrome (DS). This study aims to assess how lifestyle factors-diet quality, nutrient intake or physical activity-contribute to weight gain. <b>Methods:</b> 230 males/females with DS, aged 12-45 years, were recruited across three geographically independent sites. A total of 185 participants were considered for this analysis and classified into normal-weight, overweight, and obese categories. Diet quality and nutrient intake were calculated using country-specific FFQs. Physical activity was assessed with the Minnesota Leisure Time Activity Questionnaire. Body composition measures were obtained with a bioimpedance scale. <b>Results:</b> The study corroborates a higher prevalence (%) of overweight/obesity in our DS cohort compared to the general population. Higher BMIs were significantly correlated with older age (<i>p</i> < 0.001), lower physical activity (<i>p</i> < 0.05), higher parental BMIs (<i>p</i> < 0.001, mother's BMI; <i>p</i> < 0.05, father's BMI), and increased adiposity indicators. Excess body weight showed an inverse association only with protein intake (<i>p</i> < 0.001). No significant differences emerged in total caloric or other macronutrients intake across BMI categories. However, notable differences in dietary patterns were observed among the three countries, reflecting cultural influences. A smaller exploratory sub-study suggested a potential relationship between higher IQ scores and better diet quality (<i>p</i> < 0.05). <b>Conclusions:</b> These findings provide new insights into contributors to overweight/obesity in DS people, indicating an influence of age, physical activity, familial factors, and body composition. Higher protein intake and culturally adapted lifestyle interventions may contribute to improving weight-related outcomes.