Loss of neuronal population organization links pathology to behavior in a model of Alzheimer’s disease

Abstract Alzheimer’s disease (AD) and related dementias (ADRD) are defined by molecular and cellular pathology and cognitive decline, but linking these levels requires understanding how pathology alters large-scale neuronal activity. We longitudinally tracked behavior, multi-area neuronal population activity, and fluid and histological biomarkers in a macaque model of early-stage ADRD. As pathology progressed, visually guided behavior became increasingly disorganized, reflected in less structured exploration despite preserved task performance. Guided by systems neuroscience principles linking neuronal population activity with organized goal-directed behavior, we found progressive reductions in coordinated neuronal population activity within and between visual and parietal cortices, even as single-neuron tuning and basic feature encoding remained stable. These changes emerged when tau pathology was largely confined to regions providing feedback to visual cortex. This disorganized state appears modifiable: proof-of-concept methylphenidate administration was associated with transient improvement in behavioral organization. Together, these findings identify disruption of neuronal population organization as a defining feature of early-stage ADRD and frame early dysfunction as a disorder of coordinated population activity.