Cortico-white Matter Functional Coupling as a Biomarker of Alzheimer's Disease Progression and rTMS Therapeutic Efficacy.
INTRODUCTION Alzheimer's disease (AD) spectrum disorders are characterized by progressive cognitive decline, with white matter degeneration and disrupted cortico-cortical connectivity as early features. Cortico-white matter functional coupling integrates neuronal activity with axonal conduction, yet its natural trajectory across the AD spectrum and ability to be modulated by repetitive transcranial magnetic stimulation (rTMS) remain unclear. METHODS Longitudinal resting-state fMRI from the ADNI cohort (n = 160: 59 cognitively normal, CN; 65 mild cognitive impairment, MCI; 36 AD) was used to assess baseline and 1-year changes in mean Fisher's z-transformed coupling between 82 cortical seeds (AAL-90 atlas, excluding subcortical nuclei) and a probabilistic group white matter mask. Specifically, 54 patients with amnestic MCI (aMCI) from the rTMS cohort were allocated to active (n = 40) or sham (n = 14) groups and received four weeks of neuronavigated rTMS targeting the left angular gyrus. Cortico-white matter functional coupling was calculated identically in both cohorts. Changes in coupling strength and their associations with changes in neuropsychological performance were examined across all cortical seeds. RESULTS At baseline, mean cortico-white matter functional coupling followed a nonlinear pattern (MCI > AD and CN). One-year follow-up revealed that the CN group exhibited a slight decrease in coupling, and the MCI and AD groups showed a pathological increase. Compared with the sham group, active rTMS significantly attenuated this increase in coupling. After adjusting for covariates, coupling changes were strongly correlated with cognitive decline. The AD group demonstrated the most significant associations (n = 104), whereas the active rTMS group showed 71 associations, predominantly linked to objective memory improvement. DISCUSSION This abnormal overcoupling, leading to compensation and decompensation, is associated with the progression of Alzheimer's disease. rTMS effectively moderates this pathological surge by enhancing neural efficiency and stabilizing large-scale network integration. Our findings position cortico-white matter functional coupling as an effective indicator of disease intensity and a measurable link in the chain of rTMS effectiveness for early-stage AD. CONCLUSION Overall, cortico-white matter functional coupling may serve as a novel scan-based biomarker for tracking AD progression and evaluating rTMS treatment efficacy in patients with MCI.