Hengda He, Christian G Habeck, Yaakov Stern
As one of the earliest pathological events in Alzheimer's disease, amyloid-beta accumulation has been linked to alterations in large-scale brain networks, especially the default mode network. While most prior work has focused on resting-state functional connectivity or task-evoked activation, how amyloid-beta relates to task-modulated connectivity that directly supports behaviour is less explored. Here, we examined the relationship between amyloid-beta burden and task-modulated connectivity during a Letter-Sternberg verbal working memory task in 84 cognitively normal older adults from an ongoing longitudinal cohort (aged 56-71 years; 41 females). To further understand these connectivity alterations, we tested whether these connections were associated with task performance or with cognitive reserve proxies. We found that higher amyloid-beta burden was associated with reduced connectivity-specifically during the probe-phase of working memory retrieval. At the regional scale, lower node strength in posterior-medial regions of the default mode network was related to worse task performance and mediated the amyloid-behaviour relationship. At the network scale, altered coupling between the default mode and dorsal attention networks was related to task performance but did not mediate the amyloid-behaviour relationship. Moreover, physical activity was associated with network-level coupling but not with regional node strength. These findings suggest that amyloid-beta burden disrupts retrieval-related working memory systems, particularly regions of the default mode network, while coupling between the default mode and dorsal attention networks is related to physical activity, a cognitive reserve proxy. Collectively, task-modulated connectivity provides insight into pathways through which early Alzheimer's disease pathology influences working memory performance and may inform targeted lifestyle or neuromodulation interventions for older adults.