Uncovering Biologically Coherent Peripheral Signatures of Health and Risk for Alzheimer's Disease in the Aging Brain

Brain aging is a multifaceted process that remains poorly understood. Despite significant advances in technology, progress toward identifying reliable risk factors for suboptimal brain health requires realistically complex analytic methods to explain relationships between genetics, biology, and environment. Here we show the utility of a novel unsupervised machine learning technique - Correlation Explanation (CorEx) - to discover how individual measures from structural brain imaging, genetics, plasma, and CSF markers can jointly provide information on risk for Alzheimer's disease (AD). We examined 829 participants (M _age: 75.3 ± 6.9 years; 350 women and 479 men) from the Alzheimer's Disease Neuroimaging Initiative database to identify multivariate predictors of cognitive decline and brain atrophy over a 1-year period. Our sample included 231 cognitively normal individuals, 397 with mild cognitive impairment (MCI), and 201 with AD as their baseline diagnosis. Analyses revealed latent factors based on data-driven combinations of plasma markers and brain metrics, that were aligned with established biological pathways in AD. These factors were able to improve disease prediction along the trajectory from normal cognition and MCI to AD, with an area under the receiver operating curve of up to 99%, and prediction accuracy of up to 89.9% on independent "held out" testing data. Further, the most important latent factors that predicted AD consisted of a novel set of variables that are essential for cardiovascular, immune, and bioenergetic functions. Collectively, these results demonstrate the strength of unsupervised network measures in the detection and prediction of AD.