Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease
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The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ(42) levels was independent of the APOE ε4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ε4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ε4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10(-9)).
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Human studies of cerebrospinal fluid with various Alzheimer disease-related outcomes are conflicting, including differences in APOE genotype stratified analyses.
“Human studies of cerebrospinal fluid with various Alzheimer diseaseerelated outcomes are conflicting, including differences in the APOE genotype stratified analyses [105,106].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [105]
Levels of apoE in human cerebrospinal fluid display a genotype-dependent pattern similar to the pattern in plasma.
“However, levels of apoE in human cerebrospinal fluid do display genotype-dependent pattern similar to the pattern in plasma, further murine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid [105,112,113].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [105]
Murine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid.
“However, levels of apoE in human cerebrospinal fluid do display genotype-dependent pattern similar to the pattern in plasma, further murine interstitial fluid was observed to have genotype-dependent apoE levels similar to the pattern in cerebrospinal fluid [105,112,113].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [105]
Levels of apoE in human cerebrospinal fluid display a similar genotype-dependent pattern as in plasma.
“Levels of apoE in human cerebrospinal fluid display a similar genotype-dependent pattern as in plasma,64”
Before this study, no large genome-wide association study on plasma ApoE level had been reported; only a small GWAS of 570 subjects had identified the known APOE region signal.
“Previously a small genome-wide association study (GWAS) was carried out on only 570 subjects with plasma ApoE level that identified only the known signal in the APOE region [16].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [16]
CSF ApoE level is under similar genetic control of the APOE 2/3/4 polymorphism as in plasma.
“CSF level is under the similar genetic control of the APOE 2/3/4 polymorphism as in plasma [16].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [16]
CSF apolipoprotein E levels are an endophenotype for Alzheimer's disease.
“We have previously shown that CSF APOE levels are an endophenotype for AD (Cruchaga, et al., 2012)”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as Cruchaga, et al., 2012
CSF levels of APOE protein have been suggested to act as a valuable endophenotype for AD.
“CSF levels of APOE protein have also been suggested to act as a valuable endophenotype for AD [215], along with levels of various additional proteins, the clinical and biological relevance of which remain to be elucidated [216–218].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [215]
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Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits
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- Authors
- Cruchaga, C., Kauwe, J. S. K., Nowotny, P., Bales, K., Pickering, E. H., Mayo, K., Bertelsen, S., Hinrichs, A., Fagan, A. M., Holtzman, D. M., Morris, J. C., & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Brigham Young University (US)
- Pfizer (United States) (US)
- Corresponding author
- Goate, Alison M.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-07-20
- Volume
- 21
- Issue
- 20
- Pages
- 4558-4571
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3459471
- OpenAlex
- W2147472495
- Cited by
- 207
- References
- 58
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 22 · 2021: 12 · 2020: 19 · 2019: 15 · 2018: 12 · 2017: 12 · 2016: 26 · 2015: 19 · 2014: 19 · 2013: 13 · 2012: 1
- FWCI
- 11.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (GR082604MA)
- National Institutes of Health (5u01ag024904-10, 5p30ns069329-02)
- Canadian Institutes of Health Research
- National Institute on Aging (U01-AG-024904, P30AG010129, K01AG030514, R01AG035083, U01AG032984, P 50 AG05681, P50AG005681)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, P30 NS069329-01)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, cerebrospinal fluid biomarkers, endophenotypes, Alzheimer's disease, amyloid-beta 42, APOE ε4 genotype, genetic variants, lipid metabolism, Mendelian randomization, Clinical Dementia Rating
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Genotype, Humans, Male, Middle Aged, Phenotype, Case-Control Studies
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