Differential default-mode network effective connectivity in young-onset Alzheimer’s disease variants

Abstract Late-onset Alzheimer’s disease is consistently associated with alterations in the default-mode network (DMN)—a large-scale brain network associated with self-related processing and memory. However, the functional organization of DMN is far less clear in young-onset Alzheimer’s disease (YOAD). We assessed resting-state DMN effective connectivity in two common YOAD variants (i.e., amnestic variant (n = 26) and posterior cortical atrophy (n = 13) and healthy participants (n=24) to identify disease- and variant-specific connectivity differences using spectral dynamic causal modelling. Patients with the amnestic variant showed increased connectivity from prefrontal cortex to posterior DMN nodes relative to healthy controls, whereas patients with posterior cortical atrophy exhibited decreased posterior DMN connectivity. Right hippocampus connectivity differentiated the two patient groups. Furthermore, disease-related connectivity alterations were also predictive of group membership and cognitive performance. These findings suggest that resting-state DMN effective connectivity provides a new understanding of neural mechanisms underlying the disease pathology and cognition in YOAD.