Fig. 6: The effect of p-tau and Aβ on connectivity-mediated synaptic loss.

The line charts illustrated the interaction effect estimated from linear mixed effect regressions between plasma p-tau181 level and the functional connectivity (i.e., Q1-Q4) to epicenters (first row) on mean SV2A-PET w-scores, and global AV45-PET SUVR and functional connectivity to epicenters on mean SV2A-PET w-scores (second row) respectively in pooled sample (a, c, n = 88) and Aβ+ subjects (b, d, n = 56). The scatterplots show that associations estimated from linear regressions between connectivity-based SV2A-PET w-score (β values derived from subject-level linear regression) and the concentration levels of plasma p-tau181 (first row), as well as global AV45-PET SUVR (second row), respectively among pooled sample (a, c) and Aβ+ subjects (b, d). e The mediation effect of plasma p-tau181 concentration on the association between global AV45-PET SUVR and connectivity-based SV2A w-score among the pooled sample. f The presence of Aβ plaques (4G8 staining), relatively lower intensities of SV2A, and tau (AT8 staining, green) in postmortem brain tissue of entorhinal cortex from AD patients (n = 5) than in the controls (n = 4). Nuclei were counterstained with DAPI (white). Scale bars = 2000 μm (row 1, 3) and 50 μm (row 2, 4). g Significantly reduced levels of SV2A and increased levels of AT8 were found in the entorhinal cortex of AD patients compared to those in the controls indicated by Mann-Whitney test. Bar heights represent group means, and error bars represent ±1 standard error of the mean (SEM). h The association between the levels of AT8 and SV2A is tested using Spearman correlation. Linear model fits are indicated together with 95% confidence intervals. The statistical significance is assessed using two-sided tests. Source data are provided in a Source data file.