TY - JOUR

T1 - Plasma apolipoprotein E levels and risk of dementia

T2 - A Mendelian randomization study of 106,562 individuals

AU - Rasmussen, Katrine L

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Børge G

AU - Frikke-Schmidt, Ruth

N1 - Copyright © 2017. Published by Elsevier Inc.

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.jalz.2017.05.006

DO - 10.1016/j.jalz.2017.05.006

M3 - Journal article

C2 - 28774656

VL - 14

SP - 71

EP - 80

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

SN - 1552-5260

IS - 1

ER -