Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits

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 linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans. Reagh et al. identify a novel mechanistic pathway for the decline in pattern separation of object stimuli observed with aging—a network dysregulation characterized by hypoactivity in the anterolateral entorhinal cortex and hyperactivity in the dentate and CA3 subregions of the hippocampus. This novel biomarker yields a potential tool for assessing the neural basis of age-related memory decline.