Taken together, the present findings suggest that greater functional connectivity between medial temporal lobe and neocortical regions in the absence of AD pathology is in fact beneficial for cognitive function, but the presence of Aβ and/or ApoE4 genotype may alter the excitatory/inhibitory balance of neural circuits along robust functional connections (Harris et al. 2020; Ranasinghe et al. 2022), leading to the spread of pathological tau protein and subsequent cognitive decline. Here, APOE is linked to Alzheimer disease.