EDUCATION AND MORTALITY IN INDIVIDUALS WITH ALZHEIMER NEUROPATHOLOGY: A TEST OF THE COGNITIVE RESERVE HYPOTHESIS
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Background: The cognitive reserve hypothesis describes a hypothetical mechanism to cope with brain damage: individuals with high reserve are thought to tolerate more Alzheimer neuropathology before symptom onset, show greater neuropathology at time of onset, and experience shorter survival post onset. This study assessed the association of educational attainment and academic performance, variables influencing reserve, with overall survival and examined whether Alzheimer neuropathology modified this association. Methods: Analyses were based on the Nun Study, a longitudinal study of aging in 678 participants aged 75+ years at baseline. Data on highest level of educational attainment and first-year high school grades in English, Latin, Algebra, and Geometry, available from the convent archives, were used as measures of education and academic performance, respectively. Alzheimer neuropathology was assessed in postmortem autopsies according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) and National Institute on Aging and Reagan Institute (NIA-RI) neuropathologic criteria. Cox proportional hazards regression models included cognitive status as a time-dependent covariate; age and apolipoprotein E (APOE), a genetic risk factor for Alzheimer’s disease, as time-independent covariates; and Alzheimer neuropathology as an effect modifier. Results: In unadjusted models, educational attainment (Bachelor’s degree vs. high school or less: HR=0.88, 95% CI=0.49-1.56; Master’s degree vs. high school or less: HR=0.81, 95% CI=0.45-1.44) and academic performance (Quartile 2 vs. Quartile 1: HR=0.79, 95% CI=0.55-1.14; Quartile 3 vs. Quartile 1: HR= 0.75, 95% CI=0.52-1.08; Quartile 4 vs. Quartile 1: HR=0.83, 95% CI=0.58-1.21) were not significantly associated with overall survival. After adjusting for age, APOE-ε4 status, and cognitive status, the association of educational attainment (Bachelor’s degree vs. high school or less: HR=0.96, 95% CI=0.54-1.71; Master’s degree vs. high school or less: HR=1.03, 95% CI=0.57-1.86) and academic performance (Quartile 2 vs. Quartile 1: HR=0.73, 95% CI=0.50-1.06; Quartile 3 vs. Quartile 1: HR=0.76, 95% CI=0.53-1.10; Quartile 4 vs. Quartile 1: HR=0.89, 95% CI=0.61-1.29) with survival remained statistically non-significant. Results from models stratified by Alzheimer neuropathology, based on either the CERAD or the NIA-RI neuropathologic criteria, illustrated that the relationship of educational attainment and academic performance with survival was not modified by Alzheimer neuropathology. Discussion: It was hypothesized that (1) educational attainment and academic performance would be positively associated with survival in the overall population and, (2) the above association(s) would be modified by the presence of Alzheimer neuropathology. In the absence of Alzheimer neuropathology, high educational factors were hypothesized to be associated with longer survival. Conversely, in the presence of Alzheimer neuropathology, high educational factors were expected to be associated with shorter survival; this hypothesis was based upon the cognitive reserve hypothesis. If educational attainment and academic performance contribute to levels of reserve, then those with higher levels of these educational factors should tolerate more Alzheimer neuropathology before they express symptoms of AD, have more severe neuropathology when they first express symptoms of AD, and consequently have a shorter survival. The results do not support the study hypotheses; however, there are several reasons that could explain the inconsistencies with previous research: (1) differences in research methodology, (2) limited variation for the educational factors, (3) the relationship between education and survival is less established in older cohorts, such as the Nun Study population and, (4) educational factors are not significantly associated with survival in a population is homogeneous for many environmental and lifestyle factors throughout adult life. Overall, since the study results did not support our hypotheses, the research project did not find evidence to support the cognitive reserve hypothesis. Although we did not find evidence to support our hypotheses, this study contributed to our understanding of the mechanisms through which education influences survival. While not explored directly, our findings suggest that educational factors may influence survival through an alternate mechanism (i.e., other than cognitive reserve); high education may contribute to the accumulation of social and economic resources, and this in turn may influence survival. The above theory may explain why we did not find a statistical association between education and survival in a population that is homogeneous for factors such as income, housing, and access to healthcare. Furthermore, this study contributed to our understanding of the effect of educational factors on survival (since previous research presented conflicting results on this association of interest), and further allowed us to compare the differential effect of education on survival versus other health outcomes.