Anterolateral entorhinal-hippocampal imbalance in older adults disrupts object pattern separation

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer’s disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally link this condition to previously reported dentate/CA3 hyperactivity, both of which were associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans.