Whole-brain functional connectivity predicts regional tau PET in preclinical Alzheimer’s disease

Preclinical Alzheimer’s disease (AD), characterized by the abnormal accumulation of amyloid prior to cognitive symptoms, presents a critical opportunity for early intervention. Past work has described functional connectivity changes in preclinical disease, yet the interplay between AD pathology and the functional connectome during this window remains unexplored. We applied connectome-based predictive modeling to investigate the ability of resting-state whole-brain functional connectivity to predict tau (18F-flortaucipir) and amyloid (18F-florbetapir) PET binding in a preclinical AD cohort (A4, n =342, age 65-85). Separate predictive models were developed for each of 14 regions, and model performance was assessed using a Spearman’s correlation between predicted and observed PET binding standard uptake value ratios. We assessed the validity of significant models by applying them to an external dataset, and visualized the underlying connectivity that was positively and negatively correlated to posterior cingulate tau binding, the most successful model. We found that whole brain functional connectivity predicts regional tau PET, outperforming amyloid PET models. The best performing tau models were for regions affected in Braak stage IV-V regions (posterior cingulate, precuneus, lateral occipital cortex, middle temporal, inferior temporal, and Bank STS), while models for regions of earlier tau pathology (entorhinal, parahippocampal, fusiform, and amygdala) performed poorly. Importantly, tau models generalized to a symptomatic AD cohort (ADNI; amyloid positive, n = 211, age 55-90), in tau-elevated but not tau-negative individuals. For the posterior cingulate A4 tau model, the most successful model, the predictive edges positively correlated with posterior cingulate tau predominantly came from nodes within temporal, limbic, and cerebellar regions. The most predictive edges negatively associated to tau were from nodes of heteromodal association areas, particularly within the prefrontal and parietal cortices. These findings reveal that whole-brain functional connectivity predicts tau PET in preclinical AD and generalizes to a clinical dataset specifically in individuals with abnormal tau PET, highlighting the relevance of the functional connectome for the early detection and monitoring of AD pathology.