Plasma Levels of Apolipoprotein E and Risk of Dementia in the General Population

ObjectiveThe apolipoprotein E (APOE) epsilon 4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis. MethodsUsing 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of epsilon 2/epsilon 3/epsilon 4 APOE genotype. ResultsMultifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends<1 x 10(-6)). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval [CI]=2.04-3.52) and 1.80 (95% CI=1.52-2.13) for Alzheimer disease and all dementia, respectively. After further adjustment for epsilon 2/epsilon 3/epsilon 4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend=0.007) and all dementia (p for trend=0.04). Plasma apoE tertiles did not interact with epsilon 2/epsilon 3/epsilon 4 APOE genotype on risk of Alzheimer disease (p=0.53) or all dementia (p=0.79). In a subanalysis, the -219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for epsilon 2/epsilon 3/epsilon 4 APOE genotype (HR=1.56, 95% CI=1.05-2.30). InterpretationLow plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of epsilon 2/epsilon 3/epsilon 4 APOE genotype. This is clinically relevant, because no plasma biomarkers are currently implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker. Ann Neurol 2015;77:301-311