AbstractBackgroundThe characteristic spatial pattern of Aβ and p‐tau distribution suggests that pathology spreads from brain regions exhibiting pathology to interconnected regions through large‐scale axonal networks. Advances in MRI and graph theory have made it possible to study brain network organization. The current study aims to assess whether local proteinopathy and/or axonal degeneration contributes to regionally altered network measures of integration and segregation in clinically‐defined and pathologically‐confirmed Alzheimer’s disease (AD) and control brain donors.MethodPostmortem In‐situ 3T‐MRI (3DT1 and DTI) data were collected for 25 AD (6F/19M, 66y±11y) and 14 control (7F/7M, 72y±8y) brain donors. Following probabilistic tractography and structural network reconstruction, graph theoretical measures of integration (eigenvector centrality) and segregation (clustering coefficient) were calculated. After autopsy, the middle frontal gyrus (MFG), middle temporal gyrus (MTG), precuneus and middle hippocampus were immunostained for amyloid‐beta (Aβ), phosphorylated tau (p‐tau) and neurofilament light (NfL), and quantitative area% load was determined. Clinical Dementia Rating (CDR) scores were obtained from clinical records. Group differences were assessed with linear models and regional associations with Spearman and Pearson correlations, corrected for age, gender, and postmortem delay.ResultIn AD, no differences were observed in Aβ, p‐tau and NfL load among the selected neocortical regions, the hippocampus had lower Aβ and NfL load. Compared to controls, the AD group showed lower integration (p = 0.078) of the MTG, associated with higher CDR scores (r = ‐0.50;p = 0.035), more p‐tau pathology (r = ‐0.61;p = 0.002) and axonal damage (r = ‐0.64;p = 0.001). Furthermore, higher segregation (p = 0.006) of the MTG was observed and associated with higher p‐tau burden (r = 0.51;p = 0.015). In contrast, the precuneus showed higher integration (p = 0.038) and lower segregation (p = 0.023) in AD compared to controls, associated with less axonal damage (r = ‐0.44;p = 0.036) and less p‐tau pathology (r = 0.46;r = 0.033) respectively. No effects were found for the MFG and hippocampus.ConclusionIn AD decedents, a reorganization of the structural network is observed, predominantly in the parietal‐temporal region; while the temporal region is more disconnected, the parietal region is more strongly connected. Our work furthermore shows that this network (dis)integration is driven by p‐tau pathology and axonal damage, and associates with cognitive outcome.