Pathological brain states in Alzheimer’s disease

Abstract

ABSTRACTDynamic and rapid reconfigurations of neural activation patterns, known as brain states, support cognition. Recent analytic advances applied to functional magnetic resonance imaging now enable the quantification of brain states, which offers a substantial methodological improvement in characterizing spatiotemporal dynamics of activation over previous functional connectivity methods. Dysfunction to the persistence and temporal transitions between discrete brain states may be proximal factors reflecting neurophysiological disruptions in Alzheimer’s disease, although this has not yet been established. Here, we identified six distinct brain states, representing spatiotemporal trajectories of coactivation at single time points, in older adults across the Alzheimer’s disease continuum. Critically, we identified a pathological brain state that reflects coactivation within limbic regions. Higher persistence within and transitions to this limbic state, at the expense of other brain states, is associated with an increased likelihood of a clinically impaired diagnosis, worse cognitive performance, greater Alzheimer’s pathology, and neurodegeneration. Together, our results provide compelling evidence that neural activity settling into a pathological limbic state reflects the progression to Alzheimer’s disease. As brain states have recently been shown to be modifiable targets, this work may inform the development of novel neuromodulation techniques to reduce limbic state persistence. This application would be an innovative clinical approach to rescue cognitive decline in the early stages of Alzheimer’s disease.