Hyperconnectivity and Connectome Gradient Dysfunction of Cerebello-Thalamo-Cortical Circuitry in Alzheimer's Disease Spectrum Disorders.

Abstract

Cerebellar functional connectivity changes have been reported in Alzheimer's disease (AD), but a comprehensive framework integrating these findings is lacking. This retrospective study investigates the cerebello-thalamo-cortical (CTC) circuit in AD, using functional gradient analysis to elucidate deficits and potential biomarkers. We analyzed data from 246 participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI-3; NCT02854033), including 58 with AD, 103 with mild cognitive impairment (MCI), and 85 cognitively normal (CN) controls, matched for age and sex. All individuals underwent comprehensive neuropsychological assessments (MMSE, MoCA, ADAS-Cog) and MRI scans. We extracted mean time series for 270 brain regions (an extended Power atlas) and computed pairwise functional connectivity, focusing on CTC circuitry. Thalamic and cerebellar connectivity gradients were derived using voxel-wise correlation matrices and the BrainSpace toolbox, defining thalamic and cerebellar masks from the Melbourne subcortical atlas and AAL atlas, respectively. ANCOVA with post hoc analyses, controlling for age and sex, was conducted to assess abnormal CTC connectivity across AD, MCI, and CN groups. LASSO regression identified edges within the CTC circuitry that significantly differed between AD and CN, MCI and CN, AD and MCI, as well as was used to construct Logistic classification model. Pearson correlations were performed to examine relationships between mean CTC connectivity, individual edges, and cognitive scores (MMSE, MoCA, ADAS-Cog). To explore the hierarchical organization of the thalamus and cerebellum, global gradient distributions were compared across groups using two-sample Kolmogorov-Smirnov tests. Additionally, ANCOVA was applied to compare subfield- and functional-level gradients of the thalamus and cerebellum among AD, MCI, and CN. False discovery rate (FDR) corrections were used, setting the statistical significance threshold was set at P < 0.05. AD and MCI individuals exhibited increased CTC connectivity compared to CN (all P < 0.05). Average CTC connectivity did not correlate with cognitive scores (P > 0.05), but specific CTC edges were correlated. LASSO regression identified 20 discriminative edges, achieving high accuracy in AD-CN classification (AUC = 0.92 training, AUC = 0.80 test). Thalamic and cerebellar gradient distributions differed significantly across groups (all P < 0.05), with specific regions showing distinct gradient scores. Five cerebellar functional networks exhibited decreased gradient scores. Significant CTC hyperconnectivity in AD and MCI compared with CN suggests early thalamic and cerebellar dysregulation. Classification analyses effectively distinguished AD vs. CN but were moderate for MCI vs. CN and limited for MCI vs. AD. Gradient analyses revealed global- and subfield-level disruptions in AD, emphasizing the role of thalamic and cerebellar interactions in cognitive decline and offering potential diagnostic markers and therapeutic targets.