Integrity of neuronal size in the entorhinal cortex is a biologic substrate of exceptional cognitive aging

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans over age 80 who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively-healthy younger individuals, cognitively-average peers (“Normal Elderly”), and individuals with amnestic Mild Cognitive Impairment (aMCI). Postmortem sections of the ERC were stained with cresyl violet to visualize neurons, and immunostained with PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was employed to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found the soma size of layer II ERC neurons in post-mortem brain specimens were significantly larger in SuperAgers compared to all groups (p<0.05)—including younger individuals 20-30 their junior (p<0.005). SuperAgers had significantly fewer stereologically quantified AD-related neurofibrillary tangles in layer II ERC than Normal Elderly (p<0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggest that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared to individuals 20-30 years younger is remarkable, suggesting that layer II ERC integrity is a biologic substrate of exceptional memory in old age. SIGNIFICANCE STATEMENT Average aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer’s disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern SuperAging Research Program studies unique individuals known as SuperAgers, 80+ year-olds who show exceptional memory at least as good as individuals 20-30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared to their cognitively-average same-aged peers, those with amnestic mild cognitive impairment—and remarkably—even compared to individuals 20-30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.