Concerted alterations of functional connectivity and WM integrity in relationship to early amyloid deposition

Background: Early amyloid deposition results in functional and structural brain alterations in predementia stages of Alzheimer's disease (AD). However, how early functional and structural brain changes are related to each other remains unclear. Investigating the simultaneous disruptions of functional-structural brain features within individuals in relation to amyloid deposition may increase our understanding of the neuropathological processes underlying AD. Method: We included 648 non-demented participants from the European Prevention for Alzheimer’s Dementia (EPAD) cohort vIMI baseline data release. The cut-off for cerebrospinal fluid (CSF) amyloid-β positivity (A+) was defined at <1000pg/mL (Elecsys assay). Functional connectivity was estimated with functional eigenvector centrality (EC) from the resting state functional MRI. White matter (WM) integrity was estimated with fractional anisotropy (FA), computed on diffusion MRI. Both measures were computed at the voxel level within the gray and white matter, respectively. First, we used linear regression models to investigate differences between A+ and A- participants within each modality separately, adjusting for age, sex, and site. In the whole group, we performed sparse canonical correlation analysis (sCCA) on functional and structural measures, identifying shared components between the two modalities. Individual sCCA scores were compared between amyloid groups using a generalized linear model (GLM). To evaluate this association in A+ individuals, the same sCCA analysis was performed normalizing the structural and functional matrices using the mean and SD from A- participants. Results: Sample characteristics are provided in Table 1. Differences in voxelwise EC and FA between amyloid groups are shown in Figure 1. In the whole group, sCCA analysis showed that EC in the default mode, executive and cerebellar networks covary with FA in parietal, temporal and cerebellar areas (Figure 2). sCCA projections were differentially expressed according to amyloid status (Table 2). In A+ participants, stronger association of EC in the posterior DMN and cerebellum with FA in the splenium and brainstem were found (Figure 3). Conclusion: Using a data-driven multivariate analysis, we identified concerted patterns of functional and structural changes that occur with amyloid deposition in the predementia stage. These results highlight the importance of multimodal assessment for early diagnosis.