Exploring functional connectivity patterns and their associations with amyloid and tau biomarkers across alzheimer's disease stages: a resting-state fmri study

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and hallmark biomarkers: amyloid-beta (Aβ) plaques and neurofibrillary tau tangles. Functional connectivity, assessed via resting-state functional Magnetic Resonance Imaging (fMRI), has shown associations with Aβ and tau. However, its adoption is hindered by high data dimensionality, noise, and artefact susceptibility. This study explored functional connectivity differences across clinically relevant AD groups, aiming to enhance our understanding of the link between brain function and AD neuropathology. Methods and Data Analysis: Two datasets were used for cross-sectional analyses: dataset 1 was comprised of cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia of the Alzheimer’s Disease type (DAT) participants. Dataset 2 included CU only. Whole-brain region-of-interest (ROI)-to-ROI analysis was followed by a dual-approach of Multivariate Pattern Analysis and seed-based connectivity to identify regions and measure group differences in functional connectivity patterns. We then investigated whether AD biomarkers moderate functional connectivity and cognition relationships. Lastly, network-level functional connectivity differences within and between the Default Mode network and medial temporal lobe (MTL) were measured between CU Aβ+ and Aβ- participants. Results: Multivariate Pattern Analysis revealed functional connectivity differences between two out of three group comparisons. The left thalamus, precuneus, and frontal gyri sub-regions were identified as key ROIs. Tau (more than Aβ) moderated more relationships between functional connectivity and cognition, particularly among MCI participants. In dataset 2, CU Aβ+ participants showed more relationships between MTL functional connectivity and regional tau burden. Specifically, among Aβ+, lower functional connectivity was associated with higher tau pathology, pointing towards early neurodegeneration. Conclusions: These findings enhance our understanding of the interplay between brain function and AD pathology, reinforce tau as a biomarker closely linked to functional connectivity, and identify specific brain regions and networks with potential clinical applications in early AD diagnosis and therapeutic interventions.