Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer’s Disease. The Alzheimer’s Disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer’s Disease based on high-dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for to prediction of cognitive performance.

Alzheimer’s Disease (AD) is among the most frequent neuro-degenerative diseases. Early diagnosis is essential for successful disease management and chance to attenuate symptoms by disease modifying drugs. In the past, a number of cerebrospinal fluid (CSF), plasma and neuro-imaging based biomarkers have been proposed. Still, in current clinical practice, AD diagnosis cannot be made until the patient shows clear signs of cognitive decline, which can partially be attributed to the multi-factorial nature of AD. In this work, we integrated genotype information, neuro-imaging as well as clinical data (including neuro-psychological measures) from ~900 normal and mild cognitively impaired (MCI) individuals and developed a highly accurate machine learning model to predict the time until AD is diagnosed. We performed an in-depth investigation of the relevant baseline characteristics that contributed to the AD risk prediction. More specifically, we used Bayesian Networks to uncover the interplay across biological scales between neuro-psychological assessment scores, single genetic variants, pathways and neuro-imaging related features. Together with information extracted from the literature, this allowed us to partially reconstruct biological mechanisms that could play a role in the conversion of normal/MCI into AD pathology. This in turn may open the door to novel therapeutic options in the future.

MotivationThe concept of a ‘mechanism-based taxonomy of human disease’ is currently replacing the outdated paradigm of diseases classified by clinical appearance. We have tackled the paradigm of mechanism-based patient subgroup identification in the challenging area of research on neurodegenerative diseases.ResultsWe have developed a knowledge base representing essential pathophysiology mechanisms of neurodegenerative diseases. Together with dedicated algorithms, this knowledge base forms the basis for a ‘mechanism-enrichment server’ that supports the mechanistic interpretation of multiscale, multimodal clinical data.Availability and implementationNeuroMMSig is available at http://neurommsig.scai.fraunhofer.de/Supplementary information Supplementary data are available at Bioinformatics online.