Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer’s disease stages

Alzheimer’s disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow ( < 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulation in the early stages of AD. NbM degeneration was associated with reduced gBOLD activity and spatially co-localized tau accumulation, appearing in early Braak regions during the preclinical stage, i.e., cognitively unimpaired participants with abnormal CSF markers, and extending to more advanced Braak areas during the prodromal stage, i.e., mild cognitive impairment (MCI) subjects. Our findings suggest that infra-slow gBOLD activity serves as a functional neural mediator linking subcortical degeneration to cortical tau pathology, highlighting a potential functional pathway linking subcortical and cortical pathology in early AD. This study finds that reduced infra-slow global brain activity may link degeneration of a key subcortical cholinergic region to progressive cortical tau accumulation in early Alzheimer’s disease.