Age and Alzheimer’s disease affect functional connectivity along separate axes of functional brain organization

Aging and Alzheimer’s disease (AD) are associated with alterations in functional connectivity (FC), yet their spatial and temporal characteristics remain debated. Whole-cortex functional gradients, which organize regions along axes of functional similarity, are positioned here as a framework for understanding such alterations. Across two independent cohorts (BioFINDER-2, N=973; ADNI, N=129), we demonstrate that hyper- and hypoconnectivity in both healthy aging and biomarker-confirmed AD progression coexist systematically, forming consistent spatial patterns that align with two distinct axes of brain organization. Using a combination of longitudinal and non-linear analyses, we show that the early (but not late) stages of AD pathology accumulation is associated with functional alteration along the sensory-association axis, a pattern that vanishes in later stages of AD. However, functional alteration along the sensory-association axis is associated with worse cognition throughout the AD spectrum, and even in older adults without AD pathology, suggesting that these FC patterns may reflect a general neural response to cognitive strain. Independently of AD, older age was associated with alterations instead along the executive-nonexecutive axis, a finding that was consistent throughout the adult lifespan. These findings highlight the fundamental role of intrinsic functional organization in shaping how the brain responds to aging and to AD, helping to resolve previously reported discrepancies.