Resistance to Tau and Amyloid Pathology Facilitates Super-Aging

Objectives: The phenomenon of selected individuals cognitively performing above the norm even at high age (so-called super-agers) suggests that these individuals must obtain extraordinary resistance mechanisms against brain aging processes and/or neurodegeneration. However, not much is known about age-associated molecular hallmarks of neurodegeneration in super-agers, particularly concerning proteinopathies such as the accumulation of amyloid-β and tau. Therefore, we compared the intracerebral amyloid and tau burden in vivo in a group of super-agers (SA), normal-agers (NA) and patients with mild cognitive impairment (MCI) using PET imaging.

Methods: Data used for analysis were retrieved from the Alzheimer’s Disease Neuroimaging Initiative database (http://adni.loni.usc.edu/) and included three age- and education-matched groups of 26 SA, 25 NA and 25 MCI patients, all above 80 years of age. SA were defined as individuals performing above a z-score of 1.5 over a four-year period including the time-point of the PET scan acquisitions. NA presented average (0.5 < z-score > 1.5) and MCI patients below average (z-score < 0) cognitive performance in this time period. In addition, 18 younger cognitively-normal, amyloid-negative controls (YA; M(Age)= 63.2 years) were included as reference group. [18F]AV-1451 and [18F]AV-45 scans were available for all individuals. The PET scans were pre-processed including normalization to MNI space, smoothing and intensity standardization to the cerebellum. For statistical analysis, voxel-wise comparisons (p < .001, uncorr.) and a region-of-interest (ROI) analysis (p < .05) were conducted, comparing tau and amyloid burden between the four groups, respectively. Moreover, a logistic regression was performed to identify genetic and pathophysiological factors best predicting the different aging processes.

Results: No significant differences between SA and YA were observed in terms of in vivo tau and amyloid burden. The NA group exhibited higher tau burden in inferior temporal and precuneal areas and no significant differences in amyloid burden, when compared to the YA group. The MCI patients showed both high amyloid and tau pathology burden. Differences in amyloid burden predicted NA from MCI, whereas lower tau burden and lower polygenic risk predicted SA from MCI.

Conclusions: The phenomenon of super-aging appears to be associated with the resistance to tau and amyloid pathology, which likely permits maintenance of cognitive performance despite advanced age. In turn, differences between normal aging and MCI appear to be driven by the level of amyloid burden. These results motivate further research to determine responsible resistance factors, which may also inspire the development of novel treatment concepts.