A central role for acetylcholine in entorhinal cortex function and dysfunction with age in humans and mice

Structural and functional changes in the entorhinal cortex (EC) are among the earliest signs of cognitive aging. Here, we ask whether a compromised cholinergic system influences early EC impairments and plays a primary role in EC cognition. We evaluated the relationship between loss of integrity of cholinergic inputs to the EC and cognitive deficits in otherwise healthy humans and mice. Using in vivo imaging (PET/MRI) in older humans and high-resolution imaging in wild-type mice and mice with genetic susceptibility to Alzheimer's disease pathology, we establish that loss of cholinergic input to the EC is, in fact, an early feature in cognitive aging. Through mechanistic studies in mice, we find a central role for EC-projecting cholinergic neurons in the expression of EC-related behaviors. Our data demonstrate that alterations to the cholinergic EC are an early, conserved feature of cognitive aging across species and may serve as an early predictor of cognitive status.