Katrine L Rasmussen1, Anne Tybjærg-Hansen2, Børge G Nordestgaard3, Ruth Frikke-Schmidt4. 1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark; Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark; Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark. 3. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark; Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark. 4. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark; Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: ruth.frikke-schmidt@regionh.dk.
Abstract
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.
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.
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