When brain networks crash: connectivity, slow-wave activity and neural replay in Alzheimer's disease

Brain connectivity disruption is a hallmark of neurodegenerative disorders, including Alzheimer's disease (AD), yet how network breakdown gives rise to cognitive deficits remains unclear. Here, we review the evidence bearing on three interconnected processes that have been proposed to link molecular pathology to cognitive decline. First, we summarize evidence that misfolded proteins propagate along brain connectivity pathways, making the connectome the biological substrate for disease progression. Second, we discuss the divergent trajectory reported across the AD continuum, an initial compensatory hyperconnectivity followed by progressive hypoconnectivity and network collapse, together with the accompanying oscillatory changes (intrusion of slow-wave activity and suppression of fast oscillatory rhythms). Third, we examine the proposal that these oscillatory alterations compromise neural replay mechanisms, critical for memory consolidation, representing the potential link between network dysfunction and cognitive decline. By integrating evidence from human neuroimaging, electrophysiology, and animal models in the AD field, this framework offers new perspectives for therapeutic interventions targeting brain connectivity and replay mechanisms in neurodegenerative diseases.