Cognitive reserve as a moderator of the association between brain structure and later-life behavioural symptoms across the neurocognitive spectrum.

INTRODUCTION: Cognitive reserve (CR) may buffer against the clinical manifestations of neurodegenerative disease. However, less is known about the relationship between CR and neuropsychiatric symptoms (NPS). Here, we investigated the moderation effect of CR on the relationship between AD-related cortical changes and NPS in older adults. METHODS: Data were from 455 participants across the neurocognitive spectrum in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. A composite CR score (CRS) was operationalized from measures of education, occupation, and mentally stimulating personal activities. The presence of clinically significant NPS was assessed using the Mild Behavioral Impairment Checklist. Logistic regression modelled the relationship between lower hippocampal volume or entorhinal thickness and NPS. A volume/thickness*CRS interaction term was included to assess effect modification. All models adjusted for age, sex, and cognitive status. RESULTS: The association between lower hippocampal volume and higher odds of NPS was only present among participants with low CRS (OR: 1.46, 95%CI: [0.87, 2.46], p=.01), but not in participants with greater CRS (OR: 0.61, 95%CI: [0.39, 0.97], p=.01). A similar but weaker and non-significant interaction effect was observed with lower entorhinal thickness (high CRS, OR: 1.04, 95% CI: [0.52, 2.05], p=.34; low CRS, OR=1.59, 95% CI: [0.84, 2.97], p=.34). DISCUSSION: Findings indicate that greater CR may mitigate NPS associated with lower hippocampal volume, independent of cognition, suggesting that CR may provide protective benefits beyond cognition. Future research should explore outcomes longitudinally, consider domain-specific analyses, and explore whether these findings extend to functional imaging surrogates of CR.