APOE ɛ4 and Insulin Resistance Influence Path-Integration-Based Navigation through Distinct Large-Scale Network Mechanisms.

Path integration (PI), which supports navigation without external spatial cues, is facilitated by grid cells in the entorhinal cortex. These cells are often impaired in individuals at risk for Alzheimer's disease (AD). However, other brain systems can compensate for this impairment, especially when spatial cues are available. From a graph-theoretical perspective, this compensatory mechanism might manifest through changes in network segregation, indicating shifts in distinct functional roles among specialized brain regions. This study explored whether similar compensatory mechanisms are active in APOE ε4 carriers and individuals with elevated insulin resistance, both susceptible to entorhinal cortex dysfunction. We applied a graph-theoretical segregation index to resting-state fMRI data from two cohorts (aged 50-75) to assess PI performance across virtual environments. Although insulin resistance did not directly impair PI performance, individuals with higher insulin resistance demonstrated better PI with less segregated brain networks, regardless of spatial cue availability. In contrast, the APOE effect was cue-dependent: ε4 heterozygotes outperformed ε3 homozygotes in the presence of local landmarks, linked to increased sensorimotor network segregation. When spatial cues were absent, ε4 carriers exhibited reduced PI performance due to lower segregation in the secondary visual network. Controlling cortical thickness and intracortical myelin variability mitigated these APOE effects on PI, with no similar adjustment made for insulin resistance. Our findings suggest that ε4 carriers depend on cortical integrity and spatial landmarks for successful navigation, while insulin-resistant individuals may rely on less efficient neural mechanisms for processing PI. These results highlight the importance of targeting insulin resistance to prevent cognitive decline, particularly in aging navigation and spatial cognition.