Network-level functional connectivity is associated with longitudinal tau accumulation and amyloid-dependent cognitive decline in preclinical Alzheimer's disease.

Amyloid-β and tau, pathological hallmarks of AD, silently accumulate years before clinical symptoms' onset and are associated with neuronal dysfunction and cognitive impairment. Although functional connectivity has shown promise in tracking AD proteinopathy, how large-scale brain functional connections and their temporal variability relate to longitudinal pathological and cognitive changes during the preclinical stage remains unclear. Here, we examined both static and time-varying functional connectivity across brain networks in cognitively unimpaired older adults with a family history of AD, who underwent resting-state fMRI, longitudinal amyloid- and tau-PET imaging, and decade-long neuropsychological assessments. We found that lower static connectivity across multiple large-scale networks was associated with faster longitudinal tau accumulation and, selectively in individuals with elevated amyloid burden, with accelerated cognitive decline. These associations were not observed for time-varying connectivity. Together, our results demonstrate a role of static functional network organization in early pathological and cognitive progression of AD.