Whole-brain functional connectivity predicts groupwise and sex-specific tau PET in preclincal Alzheimer's disease.

Preclinical Alzheimer's disease, characterized by the initial accumulation of amyloid and tau pathologies without symptoms, presents a critical opportunity for early intervention. Yet, the interplay between these pathological markers and the functional connectome during this window remains understudied. We therefore set out to elucidate the relationship between the functional connectome and amyloid and tau, as assessed by PET imaging, in individuals with preclinical AD using connectome-based predictive modeling (CPM). We found that functional connectivity predicts tau PET, outperforming amyloid PET models. These models were predominantly governed by linear relationships between functional connectivity and tau. Tau models demonstrated a stronger correlation to global connectivity than underlying tau PET. Furthermore, we identify sex-based differences in the ability to predict regional tau, without any underlying differences in tau PET or global connectivity. Taken together, these results suggest tau is more closely coupled to functional connectivity than amyloid in preclinical disease, and that multimodal predictive modeling approaches stand to identify unique relationships that any one modality may be insufficient to discern.