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bioRxiv · 10.64898/2025.12.21.695827

Amyloid-beta relates to default and attention network connectivity during working memory retrieval

He, H.·Habeck, C.·Stern, Y.
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Abstract

As one of the earliest pathological events in Alzheimers 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 behavior 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 eighty-four cognitively normal older adults from an ongoing longitudinal cohort (age 56-71 years; 41 female). To further understand these connectivity alterations, we tested whether these connections were associated with task performance or with cognitive reserve factors. 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-behavior 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-behavior 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 that are vulnerable to amyloid-beta, while coupling between the default mode and dorsal attention networks indexes resilience. Collectively, task-modulated connectivity provides insight into pathways through which early Alzheimers disease pathology influences working-memory performance and resilience and may inform targeted lifestyle or neuromodulation interventions for older adults.

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He, H., Habeck, C., Stern, Y.. 2025-12-22. Amyloid-beta relates to default and attention network connectivity during working memory retrieval. https://doi.org/10.64898/2025.12.21.695827

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