AIMS: To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality.

METHODS AND RESULTS: Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12-1.28) for all-cause mortality, 1.28 (1.13-1.44) for cardiovascular mortality, and 1.18 (1.05-1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01-2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92-1.03) for cardiovascular mortality and 1.01 (0.95-1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36-2.12) for dementia-associated mortality.

CONCLUSION: High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.