INTRODUCTION: Spatial navigation is emerging as a critical factor in identifying pre-symptomatic Alzheimer pathophysiology, with the impact of sex and APOE status on spatial navigation yet to be established. METHODS: We estimate the effects of sex on navigation performance in 27,308 individuals (50-70 years [benchmark population]) by employing a novel game-based approach to cognitive assessment using Sea Hero Quest. The effects of APOE genotype and sex on game performance was further examined in a smaller lab-based cohort (n = 44). RESULTS: Benchmark data showed an effect of sex on wayfinding distance, duration and path integration. Importantly in the lab cohort, performance on allocentric wayfinding levels was reduced in ε4 carriers compared to ε3 carriers, and effect of sex became negligible when APOE status was controlled for. To demonstrate the robustness of this effect and to ensure the quality of data obtained through unmonitored at-home use of the Sea Hero Quest game, post-hoc analysis was carried out to compare performance by the benchmark population to the monitored lab-cohort. DISCUSSION: APOE ε4 midlife carriers exhibit changes in navigation pattern before any symptom onset. This supports the move towards spatial navigation as an early cognitive marker and demonstrates for the first time how the utility of large-scale digital cognitive assessment may hold future promise for the early detection of Alzheimer's disease. Finally, benchmark findings suggest that gender differences may need to be considered when determining the classification criteria for spatial navigational deficits in midlife adults.

Impact of Sex and APOE Status on Spatial Navigation in Pre-symptomatic Alzheimer's disease