Blood-based systems biology biomarkers fornext-generation clinical trials in Alzheimer’s disease

Alzheimer’s disease (AD)—a complex disease showing multiple pathomechanisticalterations—is triggered by nonlinear dynamic interactions of genetic/epigeneticand environmental risk factors, which, ultimately, converge into a biologicallyheterogeneous disease. To tackle the burden of AD during early preclinicalstages, accessible blood-based biomarkers are currently being developed.Specifically, next-generation clinical trials are expected to integrate positiveand negative predictive blood-based biomarkers into study designs to evaluate,at the individual level, target druggability and potential drug resistancemechanisms. In this scenario, systems biology holds promise to acceleratevalidation and qualification for clinical trial contexts of use—includingproof-of-mechanism, patient selection, assessment of treatment efficacy andsafety rates, and prognostic evaluation. Albeit in their infancy, systemsbiology-based approaches are poised to identify relevant AD “signatures” throughmultifactorial and interindividual variability, allowing us to decipher diseasepathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopmentstrategies will be the road ahead towards effective disease-modifyingdrugs.