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Recent functional imaging studies have proposed that the human entorhinal cortex (ERC) is subdivided into functionally distinct anterolateral (alERC) and posteromedial (pmERC) subregions. The alERC overlaps with regions that are affected earliest by Alzheimer's disease pathology, yet its cognitive function remains poorly understood. Previous human fMRI studies have focused on its role in object memory, but rodent studies on the putatively homologous lateral entorhinal cortex suggest that it also plays an important role in representing spatial properties of objects. To investigate the cognitive effects of human alERC volume differences, we developed an eye-tracking-based task to evaluate intra-item configural processing (i.e., processing the arrangement of an object's features) and used manual segmentation based on a recently developed protocol to delineate the alERC/pmERC and other medial temporal lobe (MTL) subregions. In a group of older adult men and women at varying stages of brain atrophy and cognitive decline, we found that intra-item configural processing, regardless of an object's novelty, was strongly predicted by alERC volume, but not by the volume of any other MTL subregion. These results provide the first evidence that the human alERC plays a role in supporting a distinct aspect of object processing, namely attending to the arrangement of an object's component features. SIGNIFICANCE STATEMENT Alzheimer's disease pathology appears earliest in brain regions that overlap with the anterolateral entorhinal cortex (alERC). However, the cognitive role of the alERC is poorly understood. Previous human studies treat the alERC as an extension of the neighboring perirhinal cortex, supporting object memory. Animal studies suggest that the alERC may support the spatial properties of objects. In a group of older adult humans at the earliest stages of cognitive decline, we show here that alERC volume selectively predicted configural processing (attention to the spatial arrangement of an object's parts). This is the first study to demonstrate a cognitive role related to alERC volume in humans. This task can be adapted to serve as an early detection method for Alzheimer's disease pathology.

Anterolateral Entorhinal Cortex Volume Predicted by Altered Intra-Item Configural Processing