Quantifying Cognitive Reserve Through Structural-Functional Interactions: Neuroadaptive Biomarkers in Aging and Neurodegenerative Pathologies

Background: Cognitive reserve (CR) explains individual resilience to age-related cognitive decline, yet its neurobiological basis remains elusive. Current CR proxies lack direct mechanistic links, necessitating a system-level approach integrating brain structure-function interactions. Methods: We developed a novel CR metric using structural MRI and resting-state fMRI from 1,280 older adults. A youth-derived structural-functional prediction model estimated maximal attainable brain function in elders. CR was quantified as the deviation between observed and predicted function. Cross-sectional and longitudinal analyses assessed CR's spatial distribution, cognitive associations, and pathological relevance in MCI/AD cohorts. Results: CR hubs localized to prefrontal, cingulate, and precuneus regions, organized within high-order networks. Higher CR predicted slower cognitive decline (r = −0.21, p < 0.001) and correlated with reduced Aβ deposition (r = −0.63, p < 0.001). CR demonstrated domain-specific associations with memory, attention, and processing speed. MCI exhibited broader CR reductions than AD, particularly in frontotemporal regions, likely reflecting stage-specific neuroplastic dynamics: early MCI retains partial compensatory capacity but inefficient CR utilization under mounting pathological stress, whereas advanced AD transitions to irreversible structural damage that disrupts CR's adaptive "software" mechanisms. Conclusions: This study establishes CR as a dynamic neuroprotective framework, bridging functional resilience and structural integrity. CR's spatial specificity and inverse link to amyloid pathology highlight its potential as an early biomarker for resisting pathological aging.