Author Summary 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 functional connectivity impairments were higher at high global connectivity regions, preceding changes in amyloid-beta positron emission tomography 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. Abstract Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer’s 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 has not clearly distinguished between two scenarios: hub regions facing a higher risk of connectivity disruption (targeted attack) and all regions having an equal risk (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 preclinical stages, 12 years before the expected symptom onset and is amplified alongside symptomatic progression. Moreover, hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in amyloid-beta positron emission tomography cortical markers, consistent with the activity-dependent degeneration explanation. Taken together, our findings deepen 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.

Author Summary As a dynamical system, the brain can encode information at the module (e.g., brain regions) or the network level (e.g., connections between brain regions). This means that two tasks can produce the same pattern of activation, but differ in their network profile. Here we tested this using two tasks with largely similar cognitive requirements. Despite producing nearly identical macroscopic activation patterns, the two tasks produced different functional network profiles. These findings confirm prior theoretical work that similarity in task activation does not imply the same similarity in underlying network states. Abstract It is commonplace in neuroscience to assume that if two tasks activate the same brain areas in the same way, then they are recruiting the same underlying networks. Yet computational theory has shown that the same pattern of activity can emerge from many different underlying network representations. Here we evaluated whether similarity in activation necessarily implies similarity in network architecture by comparing region-wise activation patterns and functional correlation profiles from a large sample of healthy subjects ( N = 242). Participants performed two executive control tasks known to recruit nearly identical brain areas, the color-word Stroop task and the Multi-Source Interference Task (MSIT). Using a measure of instantaneous functional correlations, based on edge time series, we estimated the task-related networks that differed between incongruent and congruent conditions. We found that the two tasks were much more different in their network profiles than in their evoked activity patterns at different analytical levels, as well as for a wide range of methodological pipelines. Our results reject the notion that having the same activation patterns means two tasks engage the same underlying representations, suggesting that task representations should be independently evaluated at both node and edge (connectivity) levels.