Hyperconnectivity and connectome gradient dysfunction of cerebello-thalamo-cortical circuitry in Alzheimer’s disease spectrum disorders

Abstract Purpose: 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. Method:246 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (58 AD, 103 mild cognitive impairment [MCI], 85 normal cognitions [CN]) underwent 3T MRI. The CTC circuitry was constructed using T1 weighted imaging and resting-state functional MRI. Voxel-based gradient values were analyzed globally, in subfields, and cerebellar functional networks. Cognitive scores (MMSE, MoCA, ADAS-Cog) were assessed at each ADNI site. Statistical analyses included ANCOVA, post hoc analyses, Pearson correlations, LASSO regression, logistic regression, and Kolmogorov-Smirnov tests. False discovery rate (FDR) corrections were used, setting the statistical significance threshold was set at P < 0.05. Results: 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. Conclusions: This study provides preliminary evidence supporting CTC hyperconnectivity as a potential diagnostic biomarker for AD. It suggests the involvement of the thalamus and cerebellum in cognitive impairment in individuals with AD.