Abstract
Human cognition and behavior rely on the integration of large-scale neural networks that connect the cerebral cortex and subcortical structures. Emerging evidence suggests that alterations in the functional connectivity (FC) between the cortical and subcortical regions in Alzheimer's disease (AD) may influence the onset and progression of both cognitive and noncognitive symptoms at the group level. However, an individualized and longitudinal framework to capture deviations in subcortico-cortical FC from normative brain aging remains underexplored. We addressed this gap by leveraging large-scale longitudinal neuroimaging datasets and applying a normative modeling approach to characterize subcortical FC trajectories across the adult lifespan. First, we quantified individual deviations in the subcortical FC in individuals with cognitive impairment (CI) relative to a normative aging group using centile scores and tracked longitudinal changes across multiple follow-ups. We examined the relationship between changes in subcortical FC and clinical measures of cognitive function, including episodic memory, executive function, and language. Our findings revealed widespread decreases in the subcortical FC in individuals with CI, except in the limbic network, which diverged from the patterns observed in normal aging. These alterations are significantly associated with a decline in memory and executive functions. Collectively, our results may advance our understanding of AD-related connectopathy and provide a direction for profiling individualized longitudinal FC changes in individuals with CI. Furthermore, our results could inform individualized prognosis and targeted interventions.