Brain Fluidity as a Functional Marker of Tau-Related Neurodegeneration in Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common form of dementia and one of the leading neurodegenerative disorders worldwide. Neurophysiopathologically, AD is characterized by neuronal death, accompanied by the alteration of tau protein in the cerebrospinal fluid (CSF) and beta-amyloid plaques in brain tissue. Although significant progress has been made in identifying the biological markers of AD, a deeper understanding of how these changes lead to functional disruptions in brain dynamics - and ultimately to clinical symptoms - remains crucial. In this context, quantitative electroencephalography (qEEG) has emerged as a valuable neurophysiological tool for studying the temporal dynamics of large-scale brain activities with high temporal resolution. A growing body of research has recently focused on brain fluidity, a metric of the brain’s ability to dynamically reconfigure its functional connectivity patterns over time - reflecting its capacity for adaptive processing and cognitive flexibility. In Alzheimer’s disease, this fluidity may be altered, suggesting a reduced ability of the brain to shift between different functional states in response to internal or external stimuli. In this study, we explored alterations in brain fluidity in AD by analyzing EEG data from 28 patients with a clinical diagnosis of Alzheimer’s disease and 29 age-matched healthy controls. Following preprocessing and source reconstruction, we computed functional connectivity using the Phase Locking Value (PLV) within sliding time windows. Brain fluidity was then quantified as the average similarity between successive PLV connectivity matrices, for each canonical frequency band. Our findings reveal frequency-specific alterations of fluidity in AD patients, particularly in the theta and beta frequency bands. Moreover, we found that reduced fluidity was directly correlated with lower scores on the Mini-Mental State Examination and with higher levels of CSF biomarkers, such as the levels of total tau protein and those of phosphorylated tau. These results suggest that decreased brain fluidity may serve as a functional marker of tau-related neurodegeneration and cognitive impairment in AD. In conclusion, our study provides evidence that the temporal variability of functional connectivity, captured through EEG-based brain fluidity, represents a promising functional biomarker, potentially aiding in early diagnosis and monitoring of disease progression.