Trial-Ready Cohort-Down Syndrome (TRC-DS)

Inclusion Criteria:

1. Diagnosis of DS (including trisomy 21, mosaic trisomy 21, Robertsonian translocationtrisomy 21 or partial trisomy 21) (as confirmed by Karyotype genetic testing ormedical record review)

2. Provision of signed and dated informed consent form; this includes adults with DSwho can provide consent, or for whom an LAR provides consent on behalf of theindividual to participate. Adults with DS who cannot consent must sign and date anassent accompanied with a signed and dated consent by legally authorizedrepresentative (LAR).

3. Stated availability and willingness to comply with all study procedures andavailability for the duration of the study or until referred to a clinical trial

4. Male or female, aged 25-55 inclusive

5. In good general health as evidenced by medical history with no diagnosis of dementia

6. Permitted CNS-active medications, stable in dose for at least 4 weeks or longer. Ifnew medications have been started, medical monitoring team will review on case bycase basis to recommend timing of baseline cognitive testing

7. Adequate visual and auditory acuity to allow neuropsychological testing

8. Mental Age of 4 years or greater (based upon the Kaufman Brief Intelligence Test,Second Edition, or based upon medical records)

9. IQ equal to or greater than 40 (based upon the Kaufman Brief Intelligence Test,Second Edition)

10. Must speak English or Spanish fluently

11. Must have a reliable Study Partner (may be caregiver, sibling, parent) who iscapable of providing correct information about the participant's clinical symptomsand history

Exclusion Criteria:

1. Any significant disease or unstable medical condition that could affectparticipation (i.e., unstable psychiatric disease, unstable cardiac problems,chronic renal failure, chronic hepatic disease, severe pulmonary disease)

2. Participants in whom magnetic resonance imaging (MRI) is contraindicated including,but not limited to, those with a pacemaker, presence of metallic fragments near theeyes or spinal cord, or cochlear implant (Dental fillings do not present a risk forMRI)

3. Participants unable to complete MRI procedure

4. History, within the last 5 years of a primary or recurrent malignant disease withthe exception of non-melanoma skin cancers, resected cutaneous squamous cellcarcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situprostate cancer with normal prostate-specific antigen post-treatment

5. Clinically significant abnormalities in B12 or TFTs that might interfere with thestudy. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) andmethylmalonic acid (MMA)) indicate that it is not physiologically significant. Ahigh TSH is exclusionary unless follow up T3/T4 levels indicate that it is notphysiologically significant.

6. Clinically significant abnormalities in screening laboratories

7. For participants undergoing CSF collection: a current blood clotting or bleedingdisorder, or significantly abnormal PT or PTT at screening or if on anti-coagulationtherapy (e.g. warfarin)

8. Concurrent participation in a clinical trial for an investigational product orconcurrent participation in longitudinal study with overlapping outcomemeasures/procedures is prohibited with the exception of ABC-DS co-enrollment or asapproved by project director

9. Participants whom the investigator deems to be otherwise ineligible. TheInvestigators should consult with the Coordinating Center on any issues that maydisqualify the participant from participation in future clinical trials to determinewhether enrollment into TRC-DS would be appropriate