Integrity of Neuronal Size in the Entorhinal Cortex Is a Biological Substrate of Exceptional Cognitive Aging

Caren Nassif, Allegra Kawles, Ivan Ayala, Grace Minogue, Nathan P. Gill, Robert A. Shepard, Antonia Zouridakis, Rachel Keszycki, Hui Zhang, Qinwen Mao, Margaret E. Flanagan, Eileen H. Bigio, M. Marsel Mesulam, Emily Rogalski, Changiz Geula, Tamar Gefen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20–30 years their junior. This study investigated whether neuronal integrity in the 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. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody 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 used 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 that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p, 0.05)—including younger individuals 20–30 years their junior (p, 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer’s disease-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 suggests 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 with individuals 20–30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.

Original languageEnglish (US)
Pages (from-to)8587-8594
Number of pages8
JournalJournal of Neuroscience
Issue number45
StatePublished - Nov 9 2022


  • Alzheimer’s disease
  • SuperAging
  • entorhinal cortex
  • neurofibrillary tangles
  • neuronal integrity

ASJC Scopus subject areas

  • General Neuroscience


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