Different functional connectivity gradients reflect aging and Alzheimer’s disease

Abstract

Aging and Alzheimer’s disease (AD) are accompanied by alterations to large-scale communication patterns in the brain, which can be tracked in vivo using functional connectivity. The location, direction and relevance of these changes remain widely debated, although they are rarely studied in the context of whole-cortex communication dynamics. Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer’s Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory–association axis. Meanwhile, age-related functional changes occur along the representation–executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain. More broadly, our findings position whole-brain connectivity dynamics as a unifying framework for interpreting functional changes across the adult lifespan.