Neurophysiological trajectories in Alzheimer’s disease progression

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid- [Formula: see text] and misfolded tau proteins causing synaptic dysfunction and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. Increases in neural synchrony in the delta-theta band and decreases in the alpha and beta bands showed progressive changes along the EBM stages. Decreases in alpha and beta-band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.