Paucity of Entorhinal Cortex Pathology of the Alzheimer's Type in SuperAgers with Superior Memory Performance

Abstract

Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer's disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20-30 years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.

Keywords: Alzheimer’s disease; SuperAgers; entorhinal cortex; memory; stereology.

Figure 1

(A–D) NFTs in the ERC of a SA and age-matched cognitively average NC visualized with Thioflavin-S and PHF-1. (A,B) Thioflavin-S staining from paraffin-embedded tissue in the ERC at 10× in NC2 and SA2. (C,D) PHF-1 staining from frozen sections of ERC at 10× in NC2 and SA 2 shows comparable tangle pathology. Scale bars indicate 100 μm.

Figure 2

Stereological density (number/mm³) of Thioflavin-S-positive NFTs (A) and APs (B) in the ERC of SAs versus age-matched cognitively average NCs. The middle, upper, and lower horizontal lines in the box plot represent the median, 75th, and 25th percentiles, respectively. The end of the vertical extensions above and below the box represents the extreme value that is at most 1.5 times the interquartile range above the 75th percentile or below the 25th percentile. The “+” represents the mean. ^*P < 0.05.