The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI), we predicted that PI impairment would represent the first behavioural change in adults at risk of AD. Using immersive VR, we found that midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width – RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p – [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.

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.