Abstract
BACKGROUND AND OBJECTIVES: As the population ages, differences in cognitive abilities become more evident. We investigated key genetic and life course influences on cognitive state at age 69 years, building on previous work using the longitudinal Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). METHODS: Multivariable regressions investigated the association between 4 factors: (1) childhood cognition at age 8 years; (2) a Cognitive Reserve Index (CRI) composed of 3 markers: (i) educational attainment by age 26 years, (ii) engagement in leisure activities at age 43 years, and (iii) occupation up to age 53 years; (3) reading ability assessed by the National Adult Reading Test (NART) at age 53 years; and (4) APOE genotype in relation to cognitive state measured at age 69 years with Addenbrooke's Cognitive Examination, third edition (ACE-III). We then investigated the modifying role of the CRI, NART, and APOE in the association between childhood cognition and the ACE-III. RESULTS: The analytical sample comprised 1,184 participants. Higher scores in childhood cognition, CRI, and NART were associated with higher scores in the ACE-III. We found that the CRI and NART modified the association between childhood cognition and the ACE-III: for 30 additional points in the CRI or 20 additional points in the NART, the simple slope of childhood cognition decreased by approximately 0.10 points (CRI = 70: marginal effects (MEs) 0.22, 95% CI 0.12-0.32, p < 0.001 vs CRI = 100: MEs 0.12, 95% CI 0.06-0.17, p < 0.001; NART = 15: MEs 0.22, 95% CI 0.09-0.35, p = 0.001, vs NART = 35: MEs 0.11, 95% CI 0.05-0.17, p < 0.001). The association between childhood cognition and the ACE-III was nonsignificant at high levels of the CRI or NART. Furthermore, the e4 allele of the APOE gene was associated with lower scores in the ACE-III (β = -0.71, 95% CI -1.36 to -0.06, p = 0.03) but did not modify the association between childhood cognition and cognitive state in later life. DISCUSSION: The CRI and NART are independent measures of cognitive reserve because both modify the association between childhood cognition and cognitive state.