Plasma levels of apolipoprotein E and risk of dementia in the general population
Abstract
Objective The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis. Methods Using 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype. Results Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype (HR = 1.56, 95% CI = 1.05-2.30). Interpretation Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype. This is clinically relevant, because no plasma biomarkers are currently implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker.
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The higher APOE2 expression is likely due to feedback compensation for reduced binding of APOE2 to APOE receptors.
“and is likely due to feedback compensation for reduced binding of APOE2 to APOE receptors (24,25).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [24]
Both the ε2 and the ε4 alleles are associated with unfavorable lipid profiles.
“Both the ε2 and the ε4 alleles are associated with unfavorable lipid profiles [8][9][10][11][12][13].”
From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [12]
Low plasma levels of apoE are associated with increased risk of dementia.
“Of interest, low levels of plasma apoE per se were recently reported to be associated with increased risk of dementia, 10 , 17”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [10]
The common APOE ε4 allele is an important risk marker for Alzheimer's disease, first reported by Corder et al. and validated in major cohorts around the globe.
“thereby confirming the identification of the common APOE ɛ4 allele as an important risk marker first reported by Corder et al., 8 and since validated in major cohorts around the globe. 9 , 10”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [10]
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 [10]
In the CGPS and CCHS, APOE genotype frequencies were 0.7%, 12.4%, 2.9%, 55.8%, 25.4%, and 2.9% for ε22, ε32, ε42, ε33, ε43, and ε44, respectively.
“In the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS), the APOE genotype frequencies were 0.7%, 12.4%, 2.9%, 55.8%, 25.4%, and 2.9% for ε22, ε32, ε42, ε33, ε43, and ε44, respectively [23].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [23]
Two copies of the ε4 allele are associated with roughly an eight to ten times increased risk for Alzheimer disease.
“One copy of the ε4 allele is associated with a two to three times increased risk for Alzheimer disease, and two copies of the ε4 allele is associated with roughly an eight to ten times increased risk [23,100].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [23]
One copy of the ε4 allele is associated with a two to three times increased risk for Alzheimer disease.
“One copy of the ε4 allele is associated with a two to three times increased risk for Alzheimer disease, and two copies of the ε4 allele is associated with roughly an eight to ten times increased risk [23,100].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [23]
Low plasma levels of apoE are epidemiologically associated with increased risk of future dementia in the general population, independent of APOE genotype.
“Recently, low plasma levels of apoE was shown to be epidemiologically associated with increased risk of future dementia in the general population, and that this was independent of APOE genotype (Fig. 4), and this has now been shown in different cohorts [23,115].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [23]
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”
Both APOE ε2 and ε4 alleles are associated with unfavourable lipid profiles.
“Both ɛ2 and ɛ4 alleles are associated with unfavourable lipid profiles,12–19”
The effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts.
“Also, recently the effect of low apoE levels per se, independent of the ɛ4 allele, was observed to be associated with high risk of dementia in three independent prospective European cohorts,17,23”
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 [14]
APOE polymorphism is associated with variation in plasma ApoE concentration; APOE*4 is associated with lower and APOE*2 with higher plasma ApoE level compared to APOE*3.
“APOE polymorphism is also associated with variation in plasma ApoE concentration; APOE*4 is associated with lower and APOE*2 with higher level as compared to the common APOE*3 allele [13, 14].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [14]
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 [14]
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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
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2015-01-13
- Volume
- 77
- Issue
- 2
- Pages
- 301-311
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2100948379
- Semantic Scholar
- d3bbbc54c6e2c1d9a2e878594b60178cc78548a9
- Cited by
- 156
- References
- 45
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 14 · 2023: 13 · 2022: 16 · 2021: 4 · 2020: 15 · 2019: 22 · 2018: 12 · 2017: 16 · 2016: 16 · 2015: 9
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Danish Council for Independent Research (10-081618)
- Research Council at Rigshospitalet
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, Alzheimer's disease, dementia, APOE ε4, APOE genotype, plasma biomarkers, preclinical biomarkers, genetic risk factors
- MeSH terms
- Aged, Apolipoproteins E, Dementia, Denmark, Female, Follow-Up Studies, Humans, Male, Middle Aged, Population Surveillance, Prospective Studies, Risk Factors, Biomarkers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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