The Systemic Synuclein Sampling Study (S4) aimed to investigate the levels and distribution of the protein alpha-synuclein and other biomarkers in Parkinson’s disease. S4 data is a rich data set facilitating discovery, validation, and reproducibility in Parkinson’s disease research. The data set was generated through cross-sectional clinical measurements (health and medical history questionnaires administered by a clinic practitioner), brain imaging, and analysis of assays performed on biofluids and tissues. S4 is a cross-sectional study without longitudinal follow-up, meaning that study activities could be completed over a 16-week time period as described in the S4_Clinical Study Protocol. As part of the testing battery, biological samples including DNA, RNA, CSF, plasma, serum, whole blood, saliva, skin, colon tissue, and submandibular gland tissue were collected from participants. These samples are distributed to academic laboratories and industry groups on an ongoing basis for analysis and the resultant data are returned and are distributed to the public when they become available. As new studies are released, an updated version of this data will be posted. *Note that downloading this entire data set will require ~550 GB of storage space. Individual file sizes are included in the 'manifest.csv' file. More information on the contents of these data can be found in the 'S4_Data_Dictionary.pdf' file, which can either be downloaded on this page once your access request has been approved or here for those interested in reviewing contents of these data prior to applying. **Version 1.1 has been posted and includes additional data generated from seed amplification assay (SAA) testing on cerebrospinal fluid (CSF) and submandibular gland (SMG) samples.