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 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 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.