Fig. 7. Lower novelty-related FC between the LC and bilateral hippocampus as well as parahippocampal gyrus are associated with steeper Aβ-related PACC5 decline.

a Voxel-wise analyses relating LC- region of interest FC, PiB, and longitudinal PACC5 measurements: lower NvR functional connectivity between the LC and the bilateral hippocampus and parahippocampal gyrus is associated with greater decline on the PACC5, in particular in individuals with elevated PiB. Inference was performed using mixed-effects models including PACC5 as outcome variable, NvR LC-FC contrast estimates, time, PiB, their interactions, age, sex, and years of education as fixed effects, random intercepts for participants, and slopes for time (number of years between baseline and follow-up cognitive assessments). The maps were corrected for multiple comparisons using cluster-extent-based thresholding (number of participants n = 128 and number of observations is 753; cluster defining threshold Z > 3.1, two-tailed p < 0.05, FWER-corrected). b Visualization of the association between PACC5 performance over time and NvR FC between the LC and the group of voxels within the bilateral hippocampus and parahippocampal gyrus shown in Fig. 7a. c Visualization of the interaction between NvR LC-FC and PiB on PACC5 slopes (number of participants n = 128). The cyan box illustrates the range of PiB values at which lower NvR LC- hippocampus and parahippocampus FC is associated with PACC5 decline. In all line plots, the estimated marginal mean of the interaction terms is plotted at the mean (green), +1 SD (yellow), and −1 SD (black), but analyses were done continuously. Inference was performed using linear regression including PACC5 decline as outcome variable, and NvR LC-FC, PiB, their interaction, age, sex and years of education as predictor variables. Shaded areas around the fit lines show 95% CI. d Radar chart showing the magnitude of the associations (estimate/standard error) between NvR LC- hippocampus and parahippocampus FC and PiB-related cognitive decline on the subtests of the PACC5, as well as the executive function and memory composite scores (number of participants n = 128 and number of observations is 753). The inner orange line indicates t-value = 1.96. The outer black line indicates t-value = 10.00. More detailed results are provided in Supplementary Table 7. * Random effects were modeled using only a random intercept for each subject. Abbreviations: CAT Category Fluency Test, DSST Digit-Symbol Substitution Test, DVR Distribution volume ratio, FCSRT Free and Cued Selective Reminder Test, HIPP hippocampus, LC locus coeruleus, LM Logical Memory, MMSE Mini-Mental State Examination, PHG parahippocampal gyrus, PiB Pittsburgh Compound-B, PACC5 Preclinical Alzheimer Cognitive Composite and SD Standard Deviation.