Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals
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.
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Previous work on common APOE variants found that genetically low plasma apoE level was associated with increased risk of dementia and dementia-associated mortality.
“These findings are in accordance with our previous work on common APOE variants, where genetically low plasma apoE level was associated with increased risk of dementia and dementia‐associated mortality. 18 , 19”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [19]
Dementia diagnoses in the Danish registries have high diagnostic validity, and any unregistered events would only lead to decreased power and bias results toward the null hypothesis.
“One potential limitation concerns the validity of the dementia diagnoses; however, the national Danish Patient Registry includes all hospital visits, and dementia diagnoses in the Danish registries have high diagnostic validity 19 , 44 ; any unregistered events would only lead to decreased power of estimates and bias results toward the null hypothesis.”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [19]
Both rare and common variants in APOE contribute to plasma levels of apoE, likely mimicking brain apoE levels, and to risk of dementia in the general population.
“Hence, we now suggest that both rare and common variants in APOE contribute to plasma levels of apoE, likely mimicking brain apoE levels, and to risk of dementia in the general population. 10 , 19”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [19]
Low levels of plasma apoE have been reported to be associated with increased risk of dementia.
“Interestingly, low levels of plasma apoE were recently reported to be associated with increased risk of dementia,17,23,24 whereas high levels were associated with increased risk of ischaemic heart disease.25”
Dementia diagnoses in the Danish registries have high diagnostic validity.
“Dementia diagnoses in the Danish registries have high diagnostic validity.24,76”
Lower plasma ApoE level has been reported to be a risk factor for incident dementia and Alzheimer's disease, independent of the APOE 2/3/4 polymorphism.
“Lower plasma ApoE level has also been reported to be a risk factor for incident dementia and AD, independent of the APOE 2/3/4 polymorphism [14, 15].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [15]
Recent population-based epidemiological studies suggest that low plasma ApoE level may be a risk factor for incident dementia.
“recent population-based epidemiological studies suggest that low plasma ApoE level may be a risk factor for incident dementia [14, 15].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [15]
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<i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals
Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12165 · Cited by 64 · see citing works
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- Authors
- Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Frikke‐Schmidt, Ruth
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2017-07-31
- Volume
- 14
- Issue
- 1
- Pages
- 71-80
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W2740588875
- Semantic Scholar
- 52e81aac091bb444381fc0ee9ac57b8f6f7e2d12
- Cited by
- 75
- References
- 46
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 17 · 2021: 5 · 2020: 11 · 2019: 12 · 2018: 5 · 2017: 2
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd (10‐081618)
- Lundbeckfonden
- Rigshospitalet
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E
- MeSH terms
- Aged, Apolipoproteins E, Dementia, Denmark, Female, Genotype, Humans, Male, Middle Aged, Risk Assessment, Mendelian Randomization Analysis
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