Neuroimaging Predictors of Cognitive Resilience against Alzheimer's Disease Pathology

Abstract

Objective: Some individuals demonstrate greater cognitive resilience—the ability to maintain cognitive performance despite adverse brain-related changes—through as yet unknown mechanisms. We examined whether cortical thickness in several brain regions confers resilience against cognitive decline in amyloid-positive adults by moderating the effects of thinner cortex in Alzheimer's disease (AD)-related brain regions and of higher levels of tau. Methods: Amyloid-positive participants from the Alzheimer's Disease Neuroimaging Initiative with relevant imaging data were included (n = 160, observations = 473). Risk factors included an AD brain signature and cerebrospinal fluid phosphorylated tau. Cognitive measures were episodic memory and executive function composites. Mixed effects models tested whether region-specific cortical thickness moderated relationships between markers of AD risk and memory or executive function. Results: Cross-sectionally, thicker cortex in 8 regions minimized the negative impact of thinner cortex/smaller volume in AD signature regions on executive function. Longitudinally, higher baseline thickness in a composite of these 8 regions predicted less memory decline (p = 0.007) and weakened negative effects of phosphorylated tau on memory decline (p = 0.014), independent of baseline cognition and risk markers. Interpretation: We identified 8 cortical regions that appear to confer cognitive resilience cross-sectionally and longitudinally in the face of established indicators of AD pathology. Brain regions fostering executive function may enable compensation in later memory performance and confer cognitive resilience against effects of phosphorylated tau and AD-related cortical changes. These “resilience” regions suggest the value of focusing on brain regions beyond only those determined to be AD-related and may partially explain variability in AD-related cognitive trajectories. ANN NEUROL 2025;97:1038–1050.