Differential patterns of structural and functional disruptions of PCN and DMN-related regions: longitudinal evidence reveals cascading network dysregulation across the ad continuum

Alzheimer’s disease is clinically characterized by progressive cognitive decline, neuropsychiatric disturbances, and deterioration in social functioning and activities of daily living. During the progression of AD, the precuneus serves as one of the most densely connected hub regions in the human brain. As shown in the initial seven-network model, the precuneus is intrinsically organized into two functionally related brain networks—the default mode network and the central executive network

When the human cortical networks are further subdivided into 17 distinct networks, it becomes evident that one of them remains the well-known DMN. Another is the recently proposed “para-cingulate” network (PCN), introduced by Nicholas and his colleagues21. The PCN is a paracingulate subnetwork of the CEN, interconnected with the cingulate cortex and the core DMN, and constitutes a highly correlated task-active network located entirely within the precuneus. The PCN comprises seven specific regions, whose activations are critically implicated in the storage, retrieval, and updating of working memory. In addition, the PCN has been associated with various internally driven dynamics, such as self-referential processing, decision-making and execution in task-specific contexts, and the monitoring of internal sensations to optimize performance. It occupies a strategic position in facilitating the integration of internal and external stimuli and linking them with prior knowledge to guide subsequent behavior.

As a network closely associated with the precuneus, the PCN may play a crucial role in cognitive processes. However, its pathological alterations during the progression of AD remain largely unknown. Although the pivotal role of the precuneus in AD development has been relatively well established, little is known about how dysfunction within the associated PCN and its interactions with DMN contribute to the pathophysiological mechanisms of AD.

Based on the above, we included neurobehavioral and neuroimaging data from 153 participants in the ADNI cohort, encompassing individuals with SMC, EMCI, LMCI, and AD. Our aim was to investigate alterations in the two precuneus-related functional networks across the course of AD and to examine the temporal effects underlying these stage-dependent changes, thereby further elucidating the neurodegenerative mechanisms underlying the transition from the preclinical to the dementia stage of AD. After incorporating structural and functional imaging, as well as behavioral data from the five participant groups, we will conduct extensive analyses including VBM, functional connectivity, correlation, and temporal effects.

Our study provides important new insights into the pathophysiological basis of functional network dysfunctions closely related to the precuneus across SMC, EMCI, LMCI, and AD. For the first time, we identified that gray matter volume reductions and functional connectivity abnormalities in PCN-related regions are associated with global cognitive decline, dementia severity, and functional impairments in AD and LMCI. These findings suggest potential neuro-modulatory targets for intervention in AD-spectrum disorders. Moreover, functional connectivity and structural abnormalities in PCN regions exhibit age dependency, first emerging in AD and progressively affecting LMCI over time. We propose that this disrupted organizational pattern may serve as a reference for distinguishing early preclinical AD from LMCI/AD. Our findings demonstrate that structural and functional alterations in PCN- and DMN-related regions intensify with the severity of AD-spectrum disorders, reflecting the progressive nature of disease. In summary, this study contributes to the development of more effective therapeutic strategies and diagnostic tools to address AD and its preclinical stages.