Differential Patterns of Structural and Functional Disruptions of PCN and DMN‐Related Regions: Longitudinal Evidence Reveals Cascading Network Dysregulation Across the AD Continuum

ABSTRACT Precuneus dysfunction is a crucial biomarker of Alzheimer's disease (AD), playing a central role in AD continuum. However, the stage‐specific changes and temporal effects of structural and functional connectivity (FC) within para‐cingulate networks (PCNs), which are newly discovered and highly precuneus‐related networks across the AD continuum remain unclear. This study aimed to characterize the abnormalities in brain regions associated with PCN and default mode network (DMN) across the stages of subjective memory complaints (SMC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD, and to assess the temporal effects on the stage‐dependent changes. A total of 153 elderlies were included. Baseline and two‐year follow‐up data were collected, including demographic information (six‐month and 12‐month intervals were also collected), neuropsychological assessments, and T1‐weighted and resting‐state functional MRI. We mapped the trajectory of structural and functional abnormalities in PCN/DMN‐related regions across the AD continuum, along with their associations with neuropsychological measures. At the baseline, reduced gray matter volume (GMV) in PCN was observed exclusively in the AD, specifically in Brodmann areas 7 posterior‐medial (Ba7), Ba 23 part c/d, parieto‐occipital sulcus, and retro‐splenial cortex. After 2 years, GMV abnormalities gradually emerged in LMCI. This decline was associated with global cognitive, functional activity deficits and increased dementia severity. Reduced FC between precuneus and Ba7 was observed in AD and LMCI at 2‐year visit and was associated with dementia severity. Over time, the gap in GMV and FC within DMN/PCN‐related regions across AD continuum progressively narrowed. Functional connectivity and structural abnormalities in PCN regions exhibit age dependency, first emerging in AD and progressively affecting LMCI over time. Abnormalities in DMN can initially be observed in SMC. Both of which intensify over time and with increasing disease severity within the AD spectrum. These findings suggest that the disruption of organizational integrity of these two networks is a key factor in the progression of AD and may dynamically reflect the development of the disease.