Cognitively supernormal older adults maintain a unique structural connectome that is resistant to Alzheimer's...

Studying older adults with excellent cognitive capacities (Supernormals) provides a unique opportunity for identifying factors related to cognitive success - a critical topic across lifespan. There is a limited understanding of Supernormals' neural substrates, especially whether any of them attends shaping and supporting superior cognitive function or confer resistance to age-related neurodegeneration such as Alzheimer's disease (AD). Here, applying a state-of-the-art diffusion imaging processing pipeline and finite mixture modelling, we longitudinally examine the structural connectome of Supernormals. We find a unique structural connectome, containing the connections between frontal, cingulate, parietal, temporal, and subcortical regions in the same hemisphere that remains stable over time in Supernormals, relatively to typical agers. The connectome significantly classifies positive vs. negative AD pathology at 72% accuracy in a new sample mixing Supernormals, typical agers, and AD risk [amnestic mild cognitive impairment (aMCI)] subjects. Among this connectome, the mean diffusivity of the connection between right isthmus cingulate cortex and right precuneus most robustly contributes to predicting AD pathology across samples. The mean diffusivity of this connection links negatively to global cognition in those Supernormals with positive AD pathology. But this relationship does not exist in typical agers or aMCI. Our data suggest the presence of a structural connectome supporting cognitive success. Cingulate to precuneus white matter integrity may be useful as a structural marker for monitoring neurodegeneration and may provide critical information for understanding how some older adults maintain or excel cognitively in light of significant AD pathology.