The main objective of the AETIONOMY clinical study is to test in real clinical samples the validity of the hypothesized underlying pathogenic mechanisms of AD and PD.~Although not fully understood, the pathophysiology of neurodegenerative diseases results from the complex interplay between several biological pathways such as neuronal excitotoxicity, oxidative stress, protein miss-folding and aggregation, neuroinflammation, apoptosis etc. It is thus likely that the maps generated by the AETIONOMY project will comprise several distinct biological hypotheses and subgroups of patients defined by 1 or more of these hypotheses. The Consortium has insufficient resources to validate all these hypotheses. Although it is anticipated that the AETIONOMY Project will provide novelty in the investigators' understanding of neurodegenerative diseases, it is expected that previously known biological pathways will come out from the data mining approach, e.g. mitochondrial pathway for PD or beta-amyloid aggregation for AD. AETIONOMY project will take advantage of these previously known pathways that will be considered as internal controls. One or two novel pathogenic pathways will be tested in parallel. Overall, this strategy will allow validating two hypotheses for each neurodegenerative disease (AD and PD). As it cannot be predicted what hypotheses will precisely rise from the data mining, the approach must be adaptative. However, it is possible to anticipate which population, clinical data, brain imaging procedure, and which biological samples will have to be applied for their validation. The AETIONOMY clinical study thus aims at assembling a standardized clinical, brain imaging, and biological collection from AD patients, PD patients and healthy controls to validate the model proposed by the AETIONOMY project. The Consortium will identify potential pathogenic pathways (established and novel) involved in AD and PD and will deliver surrogate markers which serve as readouts of the involved pathways. The model will be considered validated if the selected makers allow subject stratification in the AETIONOMY clinical study according to what has been postulated in the model. Additional correlation between biomarker expression and brain imaging will be performed when available. A transversal cohort will be recruited from 4 sites in Europe (France, Germany, Spain, and Sweden), including AD and PD patients, individuals at risk of AD and PD, and healthy controls.~Approximately 655 subjects will be recruited. Subjects will have a single study visit with clinical assessments, biological sampling, brain imaging (AD group only). Standardized procedures will be used for biological sampling as well as for brain image acquisition.
The AETIONOMY project will generate a refined taxonomy and testable mechanisms underlying the derived stratification of patients.