Defining overlooked structures reveals new associations between cortex and cognition in aging and Alzheimer's disease.

Recent work suggests that indentations of the cerebral cortex, or sulci, may be uniquely vulnerable to atrophy in aging and Alzheimer's disease (AD) and that posteromedial cortex (PMC) is particularly vulnerable to atrophy and pathology accumulation. However, these studies did not consider small, shallow, and variable tertiary sulci that are located in association cortices and are often associated with human-specific aspects of cognition. Here, we manually defined 4,362 PMC sulci in 432 hemispheres in 216 human participants (50.5% female) and found that these smaller putative tertiary sulci showed more age- and AD-related thinning than larger, more consistent sulci, with the strongest effects for two newly uncovered sulci. A model-based approach relating sulcal morphology to cognition identified that a subset of these sulci was most associated with memory and executive function scores in older adults. These findings lend support to the retrogenesis hypothesis linking brain development and aging, and provide new neuroanatomical targets for future studies of aging and AD.Significance Statement Large-scale changes in cortical structure in aging suggest sulci are particularly vulnerable to atrophy. However, tertiary sulci, the smallest and most individually variable cortical folds associated with cognitive development, have not been studied in aging. Here, we investigate tertiary sulci for the first time in aging and Alzheimer's disease (AD). We find that these smaller and shallower sulci show more age- and AD-related thinning than larger sulci in posteromedial cortex (PMC), and that the atrophy of a subset of PMC sulci is most associated with cognition in older adults. These findings support classical theories linking developmental and aging trajectories at a novel anatomical resolution and provide insight into relationships between individual differences in structural brain changes and cognitive decline.