Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein Eepsilon4 (APOE-4) genetic risk for Alzheimer's disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, CA3, and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extrahippocampal activity in people with a genetic risk for Alzheimer's disease prior to the onset of cognitive deficits.
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