Relationship of cognitive reserve and APOE status to the emergence of clinical symptoms in preclinical Alzheimer's disease

The APOE epsilon 4 allele increases the risk of developing Alzheimer's disease, whereas the APOE epsilon 2 allele reduces risk. We examined whether cognitive reserve (CR), as measured by an index consisting of education, reading, and vocabulary, modifies these associations. CR was measured at baseline in 257 cognitively normal individuals (mean age 57.2 years) who have been followed for up to 17 years (mean follow-up=9.2 years). Cox regression models showed that CR and APOE epsilon 4 independently affected the risk of progressing from normal cognition to onset of clinical symptoms: CR reduced risk by about 50% in both epsilon 4 carriers and non-carriers, while epsilon 4 increased risk by about 150%. In contrast, APOE epsilon 2 interacted with CR, such that CR was more protective in epsilon 2 carriers than non-carriers. This suggests that individuals with an epsilon 2 genotype may disproportionately benefit from lifetime experiences that enhance cognition.