Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals.

Introduction: In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. Methods: Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively. Results: In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10−17 and 9 × 10−21). APOE‐weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10−300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27–1.57) for Alzheimer's disease and 1.33 (1.25–1.43) for all dementia (F‐statistics = 3821). Discussion: Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship. Highlights: Observationally low plasma apolipoprotein E is associated with risk of dementia.We studied 106,562 and 75,260 individuals using a Mendelian randomization approach.Genetically low plasma apolipoprotein E is associated with high risk of dementia.Taken together the observational and genetic estimates suggest a causal relationship. [ABSTRACT FROM AUTHOR]