APOE moderates compensatory recruitment of neuronal resources during working memory processing in healthy older adults

Abstract The APOE e4 allele increases the risk for sporadic Alzheimer's disease and modifies brain activation patterns of numerous cognitivedomains. We assessed cognitively intact older adults with a letter n-backtask to determine if previously observed increases in e4 carriers' working-memory-related brain activation are compensatory such that they serve to maintain working memoryfunction. Using multiple regression models, we identified interactions of APOE variant and age in bilateral hippocampus independently from task performance: e4 carriers only showed a decrease in activation with increasing age, suggesting high sensitivity of fMRI data for detecting changes in Alzheimer's disease–relevant brain areas before cognitive decline. Moreover, we identified e4 carriers to show higher activations in task-negative medial and task-positive inferior frontal areas along with better performance under high working memoryload relative to non-e4 carriers. The increased frontal recruitment is compatible with models of neuronal compensation, extends on existing evidence, and suggests that e4 carriers require additional neuronal resources to successfully perform a demanding working memorytask.