Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Computational simulations and animal experiments have hinted at the theory of activity-dependent degeneration as the cause of this hub vulnerability. However, two critical issues remain unresolved. First, past research hasn't disambiguated between the scenario where hub regions face a higher likelihood of connectivity disruption compared to other regions (targeted attack) and a uniformly distributed likelihood of connectivity disruption (random attack). Second, human studies offering support for activity-dependent explanations remain scarce.We refined the hub disruption index to demonstrate a hub disruption pattern in functional connectivity in autosomal dominant AD that aligned with targeted attacks. This hub disruption is detectable even in pre-clinical stages 12 years before the expected symptom onset and amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity, and sequentially followed changes observed in Aβ PET cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepened the understanding of brain network organization in neurodegenerative diseases and could be instrumental in refining diagnostic and targeted therapeutic strategies for AD in the future.

Our research introduces a refined hub disruption index that reveals early and progressive targeted connectivity impairments in brain regions central to information transfer in Alzheimer’s Disease (AD). Detectable up to 12 years before clinical symptoms, selective FC impairments were higher at high global connectivity regions, preceding changes in amyloid-beta PET markers. This supports the concept of activity-dependent degeneration and underscores the vulnerability of hub regions to neurodegenerative processes. Our findings enhance the understanding of the brain's network organization in AD and offer significant potential for improving early diagnosis and developing precise therapeutic interventions.

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Handling Editor: Gagan Wig

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A full list of members appears at the end of the manuscript in the Supplementary material

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Supplementary data