Functional Connectivity Hubs Could Serve as a Potential Biomarker in Alzheimer’s Disease: A Reproducible Study

Cortical hubs that link functionally specialized neural systems are crucial for cognition. Evidence suggests that the location and organization of hubs are related to Alzheimer’s disease (AD). However, two issues remain unclear: (i) where and how hubs change in AD, and (ii) whether hubs could be a potential pre-diagnosis biomarker for mild cognitive impairment (MCI) - a prodromal phase of AD. Accordingly, we examined the functional connectivity density (FCD) in two cohorts of resting-state functional magnetic resonance imaging (fMRI) scans (26 AD, 27 controls; 33 AD, 21 controls) and revealed consistently vulnerable FCD hub regions in AD compared with controls: within the default mode network, short-range FCD decreases in the posterior cingulate cortex and increases in the medial prefrontal cortex; within the frontal lobe, long-range FCD increases in the medial prefrontal cortex, superior frontal gyrus and middle frontal gyrus. Furthermore, FCD correlates with cognitive score and could distinguish MCI from controls with high accuracy (71.08% in dataset 1, 81% in dataset 2). By reflecting a robust and reproducible global shift in brain functions, FCD provides an fMRI biomarker for the underlying mechanism in AD.