Neurobiological mechanism in cognitive decline: from synaptic dysfunction to large-scale neural network disruption

Abstract

Neurodegenerative diseases are characterised by progressive cognitive decline, traditionally attributed to the accumulation of beta-amyloid (Aβ) and tau pathology. However, growing evidence indicates that the diseases are not only caused by synaptic dysfunction but also a syndrome of large-scale network dysconnectivity. This review synthesised current findings on how synaptic dysfunction scales up to disrupt functional connectivity across brain networks. At the microscopic level, impaired long-term potentiation, enhanced long-term depression, and AMPA receptor dysregulation compromise synaptic plasticity. These local defects extend to macroscopic network breakdown, particularly within the default mode network (DMN) and hippocampal-prefrontal circuits. Neuroimaging techniques such as resting-state fMRI and positron emission tomography (PET) reveal consistent patterns of weakened connectivity and altered synchrony that closely correlate with deficits in episodic memory, executive function, and language. Importantly, effective connectivity within DMN has been shown to predict both the incidence and timing of neurrodegenerative diseases, even years before diagnosis, underscoring its value as biomarker. Furthermore, Aβ and tau accumulation preferentially disrupt DMN, linking molecular pathology with network-level dysfunction. Together, these findings support a synapse-network model of neurodegenarative diseases such as Alzheimer’s disease, where local and global disruptions interact to drive cognitive decline. This framework highlights novel diagnostic opportunities and suggests that interventions preserving both synaptic and network integrity may hold promise for delaying disease progression.