Loss of septal cholinergic input to lateral entorhinal cortex is an early indicator of cognitive impairment.

Although alterations to central cholinergic signaling are characteristic of late-stage cognitive deficits, the early temporal profile of these alterations and their relationship to more subtle changes in cognition are less clear. In a series of translational experiments in humans and mice, we evaluated whether changes to the cholinergic system were an early feature of pathological aging. Additional studies in mice assessed the effects of selective perturbations of cholinergic signaling on cognitive performance. We focus on the cholinergic innervation of the entorhinal cortex (EC), a region that is recognized to be susceptible early in aging and neurodegenerative disease. In human studies we recruited older adult volunteers that were physically healthy and without clinical diagnosis of cognitive impairment. Participants were divided based on their cognitive status during the intake session. Using positron emission tomography (PET) with a tracer specific for the vesicular acetylcholine transporter ([