THE EARLIEST STAGES OF AMYLOID ACCUMULATION ARE ASSOCIATED WITH INCREASED FUNCTIONAL CONNECTIVITY IN NON-DEMENTED ELDERLY SUBJECTS

Abstract

We have recently found that β-amyloid (Aβ) fibrils are prone to start accumulating in cortical regions that are part of the default mode and fronto-parietal networks during the earliest stages of Alzheimer's disease (AD) (Palmqvist et al, Nature Communications, under revision). However, it is unknown how this early accumulation of Aβ fibrils affects functional connectivity and cognitive performance. We included 173 non-demented subjects (94 women, age mean±sd = 71.6±5.5 years, MMSE score = 28.6±1.5) from the Swedish BioFINDER study, all of whom exhibited non-pathological cortical composite amyloid ([18F]Flutemetamol) PET values. Further, the subjects underwent structural (T1-weighted) and functional MRI at resting state (rsfMRI, 6min, eyes closed). PET standardized uptake value ratios (SUVR) were averaged across recently identified brain regions, which are prone to the earliest amyloid accumulation (parts of default mode and fronto-parietal networks, figure 1). Structural MRIs were segmented into a gray matter volume for voxel-based morphometry analysis. Functional connectivity matrices of 840 brain regions were computed from rsfMRI data across the entire scan (static) as well as for dynamic sliding windows (exponentially weighted window length = 60s, step size = 2s). K-means cluster analysis identified six dynamic connectivity states across all subjects as best fit. Associations between Flutemetamol-binding, gray matter volume, static and dynamic functional connectivity, as well as MMSE scores were derived from linear regressions, controlling for sex, age, APOE ε4 status and clinical diagnosis (all p<0.05, corrected for multiple comparisons). A positive association between early amyloid accumulation and static functional connectivity (r=0.59), and, significantly stronger, dynamic functional connectivity (r=0.72, figure 2) was observed. A subpart of this dynamic network also showed a correlation with better global cognitive function (MMSE score; r=0.33). No significant association was found between amyloid binding and gray matter volume. We report that amyloid accumulation during the earliest stages of AD is positively associated with increased functional connectivity, which occurs independently of structural alterations. The positive relationship between functional connectivity and cognitive performance may indicate a potential compensatory mechanism of the local effects of increasing amyloid accumulation in early stages of the disease. Brain regions which are most prone to early amyloid accumulation as identified in recent analysis of the ADNI cohort (p<0.05 FWE-corrected, manuscript under revision). Association of [18F]Flutemetamol SUVR amyloid binding and resting-state dynamic functional connectivity. The connectogram schematically depicts connections with a significant association, line thickness is proportional to regression t-values (p<0.05 FWE corrected). The scatterplot shows the partial regression, hence, values are mean centered after correction for sex, age, APOe4 status and clinical diagnose.