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

Background: The AT[N] research framework focuses on three major biomarkers in Alzheimer’s disease (AD): amyloid-β deposition (A), pathologic tau (T), and neurodegeneration [N]. Objective: We hypothesize that the diverse mechanisms such as A⟶T and A⟶[N] pathways from one brain region to others, may underlie the wide variation in clinical symptoms. We aim to uncover the causal-like effect of regional AT[N] biomarkers on cognitive decline as well as the interaction with non-modifiable risk factors such as age and APOE4. Methods: We apply multi-variate statistical inference to uncover all possible mechanistic spreading pathways through which the aggregation of an upstream biomarker (e.g., increased amyloid level) in a particular brain region indirectly impacts cognitive decline, via the cascade build-up of a downstream biomarker (e.g., reduced metabolism level) in another brain region. Furthermore, we investigate the survival time for each identified region-to-region pathological pathway toward the AD onset. Results: We have identified a collection of critical brain regions on which the amyloid burdens exert an indirect effect on the decline in memory and executive function (EF) domain, being mediated by the reduction of metabolism level at other brain regions. APOE4 status has been found not only involved in many A⟶N mechanistic pathways but also significantly contributes to the risk of developing AD. Conclusion: Our major findings include 1) the region-to-region A⟶N⟶MEM and A⟶N⟶MEM pathways exhibit distinct spatial patterns; 2) APOE4 is significantly associated with both direct and indirect effects on the cognitive decline while sex difference has not been identified in the mediation analysis.