Relationship of APOE genotypes and level of cognitive reserve to cognitive trajectories among cognitively normal individuals

Abstract Background Prior findings indicate that both genetic factors and indices of cognitive reserve (CR) influence risk of cognitive decline, with APOE4 genetic status increasing risk, and APOE2 genetic status and higher CR indices decreasing risk. However, it remains unclear whether these genetic and lifestyle variables interact to influence long‐term cognitive trajectories. This study examined whether these variables modify baseline cognitive scores and longitudinal cognitive trajectories in N = 1819 participants who were cognitively normal at baseline and included in the Preclinical AD Consortium (PAC). Method PAC datasets include harmonized data from five longitudinal cohort studies: ACS, AIBL, BIOCARD, BLSA, and WRAP. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, memory, and executive function (M follow‐up = 9.8y; Table 1). APOE genotypes were coded with separate indicator variables for APOE2 (n = 233) and APOE4 (n = 581), with APOE3/3 (n = 1005) as the reference group. A CR index was calculated by combining years of education and literacy scores. Result In longitudinal mixed effect models, using time since baseline as the timescale (Table 2), higher CR index scores were associated with better baseline cognitive performance for all cognitive factor scores, but not with rate of change in cognition over time. In contrast, APOE4 genotype was associated with more negative rates of cognitive change. For the global and memory scores, there were also 3‐way CR index x APOE4 x time interactions, indicating the negative effect of APOE4 genotype on global and memory score change was attenuated among individuals with higher CR index scores (Figure 1). When the models were re‐run with the term for APOE4 genetic status reflecting the number of APOE4 alleles (i.e., 0, 1, 2; Table 3), the patterns of results were similar, except the 3‐way CR index x APOE4 x time interaction for global cognition was only marginal (p = 0.06). Conclusion Higher CR proxy scores are associated with higher levels of cognitive performance, whereas APOE4 genetic status is associated with greater rates of cognitive decline. Higher levels of CR may attenuate APOE4‐related declines in global cognition and memory, but level of CR and APOE4 have largely independent effects on executive function.