Functional neural signatures of navigation impairment in early Alzheimer’s Disease

Spatial navigation is impaired early in Alzheimer’s disease (AD), but the neural computations affected by AD pathology remain unclear. We combined virtual-reality navigation with fMRI in aged controls, preclinical AD, and early AD participants, relating navigation activity to cerebrospinal fluid biomarkers and genetic risk. Early AD was associated with dissociable alterations: amyloid- β -linked hippocampal hyperactivity during memory-demanding navigation, tau-linked reductions in hexadirectional modulation near the entorhinal cortex, and altered object-centered representations in posterior cingulate and entorhinal-adjacent regions. Object-centered changes related to how participants encoded and retrieved target locations. Hippocampal hyperactivity was the earliest, most robust effect and the only functional measure distinguishing preclinical individuals from controls. These findings connect AD biomarkers to distinct spatial computations in humans and reveal navigation-based functional signatures of neural dysfunction before overt dementia.