To rely on the anatomical organization of the hippocampal formation in understanding whether and how late‐life diseases such as diabetes and stroke contribute to age‐related cognitive decline.

Magnetic resonance imaging (MRI) was used to document brain infarcts and to generate high‐resolution functional maps of the hippocampal formation in 240 community‐based nondemented elders (mean age, 79.7 years) who received a comprehensive medical evaluation. Sixty participants had type 2 diabetes mellitus, whereas 74 had MRI‐documented brain infarcts, and the first analysis was designed to pinpoint hippocampal subregions differentially linked to each disorder. Then, guided by the results, additional functional MRI studies in aging rhesus monkeys and mice were used to test proposed mechanisms of dysfunction.

Although both diabetes and brain infarcts were associated with hippocampal dysfunction, each was linked to separate hippocampal subregions, suggesting distinct underlying mechanisms. The hippocampal subregion linked to diabetes implicated blood glucose as a pathogenic mechanism, a hypothesis confirmed by imaging aging rhesus monkeys and a mouse model of diabetes. The hippocampal subregion linked to infarcts suggested transient hypoperfusion as a pathogenic mechanism, a hypothesis provisionally confirmed by comparing anatomical patterns across subjects with infarcts in different vascular territories.

Taken together with previous findings, these results clarify how diseases of late life differentially target the hippocampal formation, identify elevations in blood glucose as a contributing cause of age‐related memory decline, and suggest specific interventions that can preserve cognitive health. Ann Neurol 2008;64:698–706