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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 (adni.loni.ucla.edu). 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: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
Human Molecular Genetics (Impact Factor: 6.68). 07/2012; 21(20):4558-4571. DOI: 10.1093/hmg/dds296
Source: PubMed

ABSTRACT 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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    • "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.
    Neurobiology of Aging 09/2014; 35:S3–S10. DOI:10.1016/j.neurobiolaging.2014.03.037 · 4.85 Impact Factor
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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.
    Neurobiology of aging 12/2013; 35(6). DOI:10.1016/j.neurobiolaging.2013.12.010 · 4.85 Impact Factor
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    • "GWAS for CSF Tau Levels Neuron 78, 256–268, April 24, 2013 ª2013 Elsevier Inc. 263 genome-wide significance level with other CSF biomarkers. We did not observe association between these SNPs and CSF levels of either APOE or Ab (Cruchaga et al., 2012), suggesting that these loci are specific for CSF tau levels and are not associated with CSF clearance or protein half life in general. Finally, the lack of association of these loci with AD risk could indicate that the association with this locus is a type I error. "
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    ABSTRACT: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10(-8) and p = 3.22 × 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10(-4), 0.039, 4.86 × 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
    Neuron 04/2013; 78(2). DOI:10.1016/j.neuron.2013.02.026 · 15.98 Impact Factor
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