Abstract
BACKGROUND: Cognitive resilience refers to an individual's capacity to cope with brain aging and pathology and to delay cognitive decline, whereas existing techniques such as functional magnetic resonance imaging capture only macroscopic features without linking them to neurophysiological mechanisms. Recent studies have shown that overexpression of the MST1 gene exacerbates Alzheimer's disease phenotypes by affecting neuronal activity and metabolism; however, its association with cognitive trajectories and imaging biomarkers remains to be further investigated. METHODS: Multimodal imaging data using information from 116 individuals with mild cognitive impairment was obtained from the ADNI database and participants from the HABS database. The correlation coefficient between glucose metabolism and neuronal low-frequency fluctuations was calculated, and residuals were derived from regression models of correlation coefficient with amyloid protein. Unsupervised clustering was then applied, and mediation analysis was conducted to investigate the mediating role of limbic orbital frontal cortex residuals in the association between MST1 gene expression and cognitive trajectories. RESULTS: Clustering identifies five groups with distinct cognitive trajectories: the high and low cognitive resilience groups exhibit slower dementia progression with lower MST1 expression, whereas the high and low cognitive vulnerability groups show faster dementia progression with higher MST1 expression. No significant differences are observed in glucose metabolism or amyloid protein levels across groups, while the limbic orbital frontal cortex residuals partially mediate the effect of MST1 gene expression on cognitive trajectories. CONCLUSIONS: Residual biomarkers can track dementia progression and characterize MST1-related pathology, providing imaging markers for assessing cognitive resilience and monitoring disease at the molecular level.