Uncovering Diverse Mechanistic Spreading Pathways in Disease Progression of Alzheimer's Disease

Abstract

AbstractBackgroundAlthough the root cause of Alzheimer's disease (AD) is largely elusive, the amyloid hypothesis has been widely used in the AD research framework, where amyloidosis induces (A biomarker) or facilitates the spread of pathologic tau (T biomarker) followed by immediate neurodegeneration ([N] biomarker) and progressive cognitive decline. As the massive heterogeneities manifested in the clinical symptoms, it is critical to understand the pathophysiological mechanism of how whole‐brain AT[N] biomarkers exert a synergistic effect on cognitive decline in the long period of disease progression.MethodTo answer this important scientific question, we employ a novel multivariate statistical inference approach to uncover the causal‐like effect of AT[N] biomarkers on cognitive decline as well as the underlying non‐modifiable risk factors through high‐dimensional neuroimaging phenotypes. Specifically, we first present a multivariate variable selection method to identify a set of brain regions where the AT[N] biomarkers exhibit strong correlations to the clinical outcomes, such as the composite scores regarding memory or executive function domains. Next, we apply mediation analysis to uncover all possible mechanistic spreading pathways of AT[N] biomarkers that lead to cognitive decline. On top of this, we further investigate the survival time for each identified (either direct or mediated) pathological pathway toward the onset of clinical symptoms, which allows us to manage the priority of risk factors more effectively in routine clinical practice.Result(1) There are several brain regions on which the amyloid burdens exert an indirect effect on cognitive decline, being mediated by the reduction of metabolism level at other topologically connected brain regions. (2) There is no overlap between memory‐specific and EF (executive function)‐specific pathways in terms of involved brain region. (3) Having two APOE ε4 alleles significantly increases the risk of developing AD in our survival model, where the odds ratio is 0.474 (p‐value: 0.01) regarding memory problem and 0.60 (p‐value: 0.002) for decline of executive functions.ConclusionWe have identified a set of mechanistic pathways in the brain where AT[N] biomarkers from multiple regions exert synergistic effect to cognitive decline. The survival rates estimated on these pathways set the stage for the precision medicine in AD treatment.