Lost in space(s): Multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.