Spatial navigation in preclinical Alzheimer's disease: A review

Alzheimer's disease (AD) develops over a prolonged preclinical phase, during which neuropathological changes accumulate long before cognitive symptoms appear. Identifying cognitive functions affected at early stages is critical for the preclinical detection of asymptomatic individuals at-risk of AD. Early risk identification could enable timely interventions aimed at mitigating the development of significant future cognitive impairment. While episodic memory decline typically appears after substantial medial temporal lobe damage, spatial navigation has emerged as a particularly sensitive cognitive function in preclinical AD. In this review, we provide an overview of spatial navigation computations and the tasks used to assess them, highlighting how spatial navigation relies on neural circuits corresponding to the earliest sites of AD pathology. We synthesize evidence from cognitively unimpaired individuals with AD biomarkers, i.e. individuals at-risk of AD, and discuss future research directions. Overall, performance on spatial navigation tasks, particularly path integration and wayfinding, correlates with plasma and CSF biomarkers of AD pathology, notably p-tau. Spatial navigation assessment can represent a sensitive and scalable approach for early detection of individuals at-risk of AD in preclinical stages, and will inform future interventions to mitigate the progression toward clinically significant cognitive impairment.