Judged by your neighbors: A novel framework for personalized assessment of brain structural aging effects in diverse populations.

Despite their promise, current neuroimaging biomarkers often fail to capture the full spectrum of inter-individual variability in brain structure and aging effects. This limits their ability to detect subtle norm deviations and impacts their utility for personalized care. We introduce Nearest Neighbor Normativity $\left({\text{N}}^3\right)$ , a novel framework designed to resolve the confound between natural diversity and subtle pathological patterns. It evaluates individual brain structures from several meaningful viewpoints, accommodates a variety of co-existing normative prototypes and accounts for individually varying progression rates of brain structural decline. Using MRI data of 36,896 individuals, we provide empirical evidence that the ${\text{N}}^3$ biomarker effectively disentangles natural inter-individual variability from pathological alterations, significantly outperforming brain age models and traditional normative modeling approaches in the detection of neurodegenerative diseases. The ${\text{N}}^3$ framework is easily adaptable to various medical domains, fostering individualized and context-rich biomarkers and paving the way for more targeted and personalized therapeutic strategies.