Network-Dependent and Amyloid-Dominant Pathways Link Early Regional Amyloid to Cognition Before Global Amyloid Positivity

Abstract Background and Objectives : Global amyloid-β (Aβ) positivity is commonly defined by thresholds intended to identify widespread cortical pathology, yet such thresholds may obscure biologically meaningful regional Aβ accumulation before individuals cross the threshold for global positivity. Here, we asked whether early regional Aβ deposition in globally Aβ-negative (gAβ−) individuals is cognitively consequential, and whether its impact depends on the brain’s network architecture. Methods Using multimodal imaging and cognitive data from the Sino Longitudinal Study on Cognitive Decline (SILCODE), we examined associations between regional Aβ burden and cognition as a function of structural and functional network topology, with longitudinal analyses within SILCODE and validation of cognitive and amyloid trajectories in the independent Harvard Aging Brain Study (HABS). Results In gAβ − individuals, regional Aβ exhibited marked heterogeneity in its cognitive relevance. Precuneus Aβ showed a topology-independent association with cognition, defining an amyloid-dominant pathway. In contrast, Aβ in several network-integrated regions including the anterior cingulate, inferior frontal gyrus pars triangularis, parahippocampal, supramarginal, postcentral, superior temporal, and middle temporal gyri was cognitively relevant primarily in relation to structural network centrality, indicating a network-dependent pathway. Longitudinally, the anterior cingulate Aβ × degree interaction predicted subsequent cognitive trajectories in SILCODE. Consistent with these findings, regional Aβ in several topology-dependent regions predicted cognitive decline over 3- and 8-year follow-up in HABS, whereas precuneus Aβ consistently predicted subsequent global amyloid progression. Conclusions Together, these findings reveal that global Aβ negativity does not necessarily signify the absence of cognitively relevant amyloid pathology. Instead, early regional Aβ may engage distinct pathways before global amyloid positivity: a precuneus-centered pathway linked to subsequent amyloid propagation and a network-dependent pathway through which local topology shapes its cognitive relevance. These results highlight the importance of regional and network-level organization for detecting and interpreting amyloid pathology below conventional global thresholds.