Education as a Proxy for Cognitive Reserve: Moderating Effects on White Matter Hyperintensity Burden in Healthy Aging and Cognitive Decline

ABSTRACT Background Cognitive reserve, often approximated by levels of education, is thought to protect against the deleterious effects of brain pathology on cognitive function. White matter hyperintensities (WMHs) are commonly associated with aging and cognitive decline, and higher WMH burden has been linked to the progression from healthy cognitive status (HC) to mild cognitive impairment (MCI). Understanding how cognitive reserve, as indicated by education, influences the relationship between WMH burden and cognitive outcomes can provide valuable insights for interventions aimed at delaying cognitive decline. Objective This study investigates the moderating role of education, as a proxy for cognitive reserve, on the relationship between WMH burden and the transition from HC to MCI. Methods Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, focusing on participants classified as cognitively healthy at baseline. A total of 153 cognitively healthy adults at the baseline were split into two groups: one group (n=85) remained cognitively healthy for at least 7 years, while the other group (n=68) progressed to MCI within 7 years. A multiple linear regression model was used to examine the interaction between group membership, baseline age, education, and sex in predicting WMH loads. The primary focus was on the interaction between group membership and education to assess the protective effect of cognitive reserve. Results The regression model explained 18.5% of the variance in WMH load. The analysis revealed statistically significant interaction between group membership and education on WMH loads (Interaction term: β = -0.097, p = 0.047), indicating that higher education levels are associated with a reduced WMH burden among individuals who progressed to MCI. The main effect of education alone was not significant, nor were the interactions involving sex (p > 0.05). Conclusion These findings support the hypothesis that education, as a proxy for cognitive reserve, provides a protective effect against the accumulation of WMH burden in older adults. The results suggest that higher cognitive reserve may mitigate the impact of neurodegenerative processes, thereby delaying the transition from HC to MCI. This underscores the importance of educational attainment in the preservation of cognitive health during aging.