Cerebrospinal fluid APOE levels: An endophenotype for genetic studies for Alzheimer's disease

Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:
Human Molecular Genetics (Impact Factor: 6.39). 07/2012; 21(20):4558-4571. DOI: 10.1093/hmg/dds296
Source: PubMed


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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Available from: Sarah Bertelsen, Jan 07, 2014
    • "Because previous functional studies linked CLU with APOE, we analyzed whether there was any correlation between CLU and APOE levels in CSF and plasma in the 537 individuals with both plasma and CSF levels (Supplemental Table 3). CLU levels in plasma and CSF were not correlated (r ¼ 0.044, p ¼ 0.311), similar to what we found previously for CSF and plasma APOE (Cruchaga et al., 2012). We found a strong correlation between CSF levels of CLU and APOE (r ¼ 0.702, p < 2.2 Â 10 À16 , Fig. 2), but the correlation in plasma was weaker (r ¼ 0.315, p ¼ 1.22 Â 10 À13 ). "
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    ABSTRACT: Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.
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    • "The original concept stems from observations made by Utermann et al. (1980) >30 years ago about the fact that humans expressing the apoE ε4/3 and apoE ε4/4 genotype display the lowest apoE blood levels of all living humans, whereas those with an apoE ε2/2 genotype (centenarian candidates ) belong to a small group of humans with the highest blood concentration of apoE (for a review, see Poirier, 2008). This is true for blood (Gupta et al., 2011; Panza et al., 2003; Poirier, 2005; Soares et al., 2012; Utermann, 1985), brain tissues (Beffert et al., 1999; Bertrand et al., 1995) (Glockner et al., 2002), and CSF (Cruchaga et al., 2012) (GWAS study in Alzheimer's Disease Neuroimaging Initiative [ADNI]) in humans and in fresh brain tissues from apoE ε4 knock-in mice (Bales et al., 2009; Sullivan, 2009) when using liquid chromatography followed by tandem mass spectrometry (LC/MS/MS) quantitative methodology. Fig. 3B summarizes key published findings. "
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    ABSTRACT: The discovery that the apolipoprotein E (apoE) ε4 allele is genetically linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain of AD subjects. The presence of the ε4 allele has been associated with lower levels of apoE in both serum and brain tissues of normal and AD subjects. In an attempt to reverse the apoE deficit in AD, we identified and characterized several apoE inducer agents using a low-throughput in vitro screening assay. The most promising of these compounds is called probucol. Administration of probucol, an old cholesterol-lowering drug, in a pilot trial in mild-to-moderate sporadic AD led to a significant increase in cerebrospinal fluid (CSF) apoE levels and a decrease in CSF in both phosphorylated tau 181 and beta-amyloid 1–42 concentrations without significant modifications of lipid hydroperoxide levels.
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    • "The TREM and TREM-like receptor genes clustered on chromosome 6p21.1 (Ford and McVicar, 2009) have different patterns of LD among them (Cruchaga et al., 2013). This genomic region has previously been implicated in genetic risk for AD (Benitez et al., 2013; Bertram et al., 2013; Cruchaga et al., 2013; Guerreiro et al., 2013; Jonsson et al., 2012; Reitz and Mayeux, 2013). A low frequency missense variant in TREM2 (p.R47H, minor allele frequency ¼ 0.003) was reported to substantially increase risk for AD (Benitez et al., 2013; Guerreiro et al., 2013). "
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    ABSTRACT: TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
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