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

BackgroundCognitive 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. MethodsWe 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 CRs spatial distribution, cognitive associations, and pathological relevance in MCI/AD cohorts. ResultsCR 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 A{beta} 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 CRs adaptive "software" mechanisms. ConclusionsThis study establishes CR as a dynamic neuroprotective framework, bridging functional resilience and structural integrity. CRs spatial specificity and inverse link to amyloid pathology highlight its potential as an early biomarker for resisting pathological aging.