Functional Hierarchy Disruption: A Mechanistic Link to Cognitive Decline and Treatment Targets in Alzheimer’s Disease

Alzheimer’s disease (AD) is marked by disrupted brain network connectivity, which impairs functional hierarchy and contributes to cognitive decline. Two fundamental questions, however, remain open: what specific changes occur in the hierarchical organization of the AD brain, and whether rectifying these changes can restore cognitive function. To answer these, we first analyzed individualized functional hierarchical architecture across three large, independent fMRI datasets (MCADI, N = 711; ADNI, N = 621; OASIS-3, N = 506). We identified a reproducible pattern of hierarchical remodeling in AD, characterized by expansion of the dorsal attention network A and shrinkage of the control network A, with spatial variability shaped by underlying brain tissue properties. To evaluate the therapeutic relevance of this signature, we conducted a randomized controlled trial of transcranial alternating current stimulation (tACS; N=44). Targeted stimulation selectively reversed the remodeling trajectory, suppressing dorsal attention network expansion and countering control network contraction. These network improvements persisted for three months and were accompanied by sustained cognitive gains, with 80% of participants showing measurable improvement. Our results reveal a functional hierarchical signature of AD and establish its potential as a novel interventional target, while also providing mechanistic insights into the action of non-invasive neuromodulation.