Damage of the temporal lobe and APOE status determine neural compensation in mild cognitive impairment

In mild cognitive impairment (MCI), the APOE4 genotype is associated with accelerated memory decline, likely due to the impact of neuropathology on main cerebral networks required for successful memory retrieval and/or to decreased capacity for recruiting secondary networks that might compensate for that brain damage. Here, we tested this hypothesis in twenty-six healthy older adults and thirty-four MCI patients, of which sixteen were APOE4 carriers. Compared to controls, MCI showed hippocampal volume reduction, cortical thinning in frontal, temporal and parietal regions, and dysfunctional EEG oscillations across fronto-temporal networks. But importantly, APOE4 status was the critical factor in determining the impact of temporal lobe degeneration on memory in MCI individuals. Specifically, path analyses revealed that hippocampal damage in MCI was responsible for memory deterioration in APOE4 carriers, a relationship mediated by the serial intervention of three related factors in noncarriers. Temporal cortical thickness (first mediator) accounted for activation of functional networks through synchronized theta activity across temporal regions (second mediator), which, in turn, coordinated memory reactivation through desynchronized alpha/beta activity across sensorimotor areas (third mediator). Results revealed that, contrary to APOE4-carrier patients, noncarriers are successful in recruiting secondary cortical networks to improve memory performance as long as the integrity and functionality of the temporal lobe is preserved, a fact primarily dependent on hippocampal degeneration.