Researchers at Washington University in St. Louis and collaborators report that in a mouse model bred to develop widespread amyloid beta plaques (the APP/PS1 model), neurons in a default-mode-network hub, the retrosplenial cortex, and two circuits it connects to lost the ability to communicate normally over time, but only in the pathway that stayed within the default mode network. A second pathway from the same starting point, running to the primary visual cortex outside that network, showed no such breakdown, even though amyloid plaques had spread broadly across the brain in both cases. The findings, published online August 31, 2026 in Nature Communications, come from long-term recordings of single neurons in freely behaving mice, tracking activity in the retrosplenial cortex, the anterior cingulate cortex, the hippocampus, and the visual cortex over an extended period as plaques accumulated. The default mode network is a set of interconnected brain regions long known from human brain scans to show both early functional decline and early amyloid buildup in Alzheimer's disease; what has been unclear is whether that network's vulnerability is simply a matter of exposure to more pathology, or whether something about the circuits themselves makes them more fragile once amyloid is present. This study was designed to test that question directly by holding one variable, the presence of widespread plaques, roughly constant while comparing what happened to connected circuits inside versus outside the network. The authors report that dysfunction was restricted to the in-network circuit and progressed over time, which they interpret as evidence for an intrinsic susceptibility of default-mode circuits rather than a simple dose-response relationship with local plaque load. The comparison is the central strength of the design: because both circuits sat in brains with comparable overall amyloid burden, the selective breakdown cannot be explained by one pathway simply seeing more plaque than the other. Outside researchers not involved in the study, and the authors themselves in earlier preprint versions of this work posted to bioRxiv, have noted that the mechanism connecting amyloid exposure to this circuit-specific fragility remains undefined; the paper describes the pattern of vulnerability without identifying what makes these particular neurons or synapses more susceptible.