Path Integration in Alzheimer's Disease: Orientation, Movement, and Theta Rhythmicity

Path integration (PI), the ability to keep track of position and orientation from self-motion, is a sensitive cognitive marker of Alzheimer's disease. While entorhinal grid cells are central to PI, we focus here on the broader functional circuit supporting PI and the impact of Alzheimer's disease within it. This circuit includes orientation from head direction cells, landmark-based error correction, and signals encoding current or intended movement direction, which we suggest may rely on theta-modulated directional cells and theta sweeps in grid and place cell firing. The early vulnerability of PI, particularly angular PI, may reflect multiple sources: pathology in the anterodorsal thalamus degrading head direction coding; disrupted theta rhythmicity and thus theta-modulated directional signals, potentially reflecting cholinergic dysfunction; and retrosplenial landmark-resetting failures allowing angular drift. We advocate for further cross-species investigation of PI tasks with electrophysiological measures to fully identify the underlying circuit mechanisms and their impairment in Alzheimer's disease.