Alzheimer’s disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.

Humans are adept in simultaneously following multiple goals, but the neural mechanisms for maintaining specific goals and distinguishing them from other goals are incompletely understood. For short time scales, working memory studies suggest that multiple mental contents are maintained by theta-coupled reactivation, but evidence for similar mechanisms during complex behaviors such as goal-directed navigation is scarce. We examined intracranial electroencephalography recordings of epilepsy patients performing an object-location memory task in a virtual environment. We report that large-scale electrophysiological representations of objects that cue for specific goal locations are dynamically reactivated during goal-directed navigation. Reactivation of different cue representations occurred at stimulus-specific hippocampal theta phases. Locking to more distinct theta phases predicted better memory performance, identifying hippocampal theta phase coding as a mechanism for separating competing goals. Our findings suggest shared neural mechanisms between working memory and goal-directed navigation and provide new insights into the functions of the hippocampal theta rhythm.

Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ϵ4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ϵ4-carriers during a virtual navigation task. We report a selective impairment in APOE ϵ4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ϵ4-carriers. Furthermore, retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.

Stress influences episodic memory formation via noradrenaline and glucocorticoid effects on amygdala and hippocampus. A common finding is the improvement of memory for central aspects of a stressful episode. This is putatively related to changes in the neural representations of specific experiences, i.e., their memory traces. Here we show that the memory improvement for objects that were encountered in a stressful episode relates to differences in the neural representations of these objects in the amygdala. Using functional magnetic resonance imaging, we found that stress specifically altered the representations of central objects: compared to control objects, they became more similar to one another and more distinct from objects that were not part of this episode. Furthermore, higher similarity of central objects to the main stressor-the faces of the stressinducing committee members-predicted better memory. This suggests that the central objects were closely integrated into a stressor-centered memory representation. Our findings provide mechanistic insights into how stress shapes the memory trace and have profound implications for neurocognitive models of stressful and emotional memory.

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