Cross-Species Imaging Applied to the Aging Brain: Dissociating Alzheimer’s Disease from Normal Aging

Whether ‘cognitive aging’ and Alzheimer's disease are overlapping processes or whether they are mechanistically distinct has been an ongoing debate. Indeed, both the early stages of Alzheimer's disease and aging itself have been found to affect the function of the hippocampal formation, a brain structure vital for memory. The hippocampal formation is made up of separate subregions, each expressing a unique molecular profile. It is this molecular anatomy that explains why mechanistically distinct processes that cause hippocampal dysfunction do so by differentially targeting select hippocampal subregions. Here, we review a series of recent studies that have applied a high-resolution variant of functional magnetic resonance imaging to map hippocampal dysfunction in human patients, aging nonhuman primates, and transgenic mouse models of Alzheimer's disease and aging. Taken together with additional postmortem observations, these studies suggest that Alzheimer's disease and aging target different subregions of hippocampal formation. More than just informing the debate over Alzheimer's disease and aging, pinpointing hippocampal subregions differentially affected by each may improve diagnostic abilities, and—more importantly—can be used to uncover pathogenic mechanisms.