Multifactor mid‐life risk for Alzheimer’s disease associated with alterations in navigation but not episodic memory: the PREVENT‐Dementia study

Abstract

BackgroundThe entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD.Method100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education.ResultIndividuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance.ConclusionThese results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD.