This study is a non-drug, multicenter, prospective cohort study. It will be conducted in 300 volunteers from 12 to 45 years of age (inclusive) with a diagnosis of Down syndrome from 3 countries (France, Spain, United Kingdom (UK)). The basic hypotheses of the study are the following:

1. Diseases (and comorbidity) arise from one or more biological networks perturbed by the genetic disorder (trisomy 21) through interaction with environmental risks factors and epigenetic changes.
2. Health comorbidity patterns in DS individuals (particularly of obesity and related conditions) will likely vary by age and sex.
3. Obesity comorbidity patterns will relate to variation in factors including lifestyle, stress-response, severity of intellectual disability (ID) and variation in cognitive domains such as executive functioning.
4. Stress responses, as measured with cortisol concentrations, will differentiate individuals with DS who are obese and those who are not. Extremes in phenotype (Obese vs. Non-obese) will be related to differences in the metabolomic, transcriptomic, and microbiome concentrations.

The study will be conducted in n= 300 volunteers with DS from 3 countries (France, Spain, UK); equal numbers in 3 age groups (12 - 18 years; 19 - 34 years; 35 - 45 years). The total number of volunteers expected to be included in each country is n = 100.

From the initial cross-sectional cohort, individuals will be selected on the basis of obesity status and invited to participate in a nested case-control study (n = 30 for normal weight DS individuals and n = 30 DS individuals with extreme phenotype). In adults, normal weight is defined as BMI 18.5 to 24.9 and significant obesity as BMI > 35 kg/m2. In children under age 18, the research team will use the International Obesity Task Force (IOTF) curves which are international norms) with IOTF > 30 for obese and IOTF 18.5 - 25 for the normal weight group. The research team will monitor allocation using monthly eCRF recruitment reports for central allocation of recruits to ensure balance between age, sex and BMI between the "cases" and the "controls".

Inclusion Criteria:

• Males and females aged 12 to 45 years
• With established genetic diagnosis of Down syndrome (full trisomy 21; based on karyotype results - not exclusion if not available but will need to confirm karyotype if not done previously)
• Availability of parent/caregiver to accompany the subject to clinical visits and to be willing to give written informed consent, when necessary

Exclusion Criteria:

• Confirmed mosaic trisomy 21, partial trisomy 21, or translocation
• Comorbid conditions - Participation is allowed as long as the condition(s) are considered stable and it do not interfere with the participation of the study
• Subjects with evidence of dementia or meeting clinical diagnoses for dementia
• Participation in a medication treatment trial in the last 3 months prior to the study

A sample of 300 individuals aged 12-45 years with a diagnosis of Down syndrome will be recruited within the 3 sites.

Participants will be recruited in three age groups stratified by sex:

• Adolescents (12-18 years; n = 100)
• Young adults (19-34 years; n = 100)
• Middle-age adults (35-45 years; n = 100).

IPD will be shared within the GO-DS21 Consortium.