Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

Dementia and Complexity in Later Life NHS Norfolk and Suffolk Foundation Trust Norfolk UK

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Norwich Medical School University of East Anglia Norwich UK

References provided by Crossref.org

Spatial navigation deficits in early Alzheimer's disease: the role of biomarkers and APOE genotype

Spatial prediction of dynamic interactions in rats

Spatial navigation questionnaires as a supportive diagnostic tool in early Alzheimer's disease

Cholinergic white matter pathways along the Alzheimer's disease continuum

Spatial navigation is associated with subcortical alterations and progression risk in subjective cognitive decline

Different Profiles of Spatial Navigation Deficits In Alzheimer's Disease Biomarker-Positive Versus Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment

Spatial Pattern Separation Testing Differentiates Alzheimer's Disease Biomarker-Positive and Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment

Early Spatial Memory Impairment in a Double Transgenic Model of Alzheimer's Disease TgF-344 AD

Basal Forebrain Atrophy Is Associated With Allocentric Navigation Deficits in Subjective Cognitive Decline

The Combined Effect of APOE and BDNF Val66Met Polymorphisms on Spatial Navigation in Older Adults