@article{e1e3a3a14b684628874db85557f9ad09,
title = "Cerebrospinal fluid APOE levels: An endophenotype for genetic studies for Alzheimer's disease",
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 Aβ42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ42 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).",
author = "Carlos Cruchaga and Kauwe, {John S.K.} and Petra Nowotny and Kelly Bales and Pickering, {Eve H.} and Kevin Mayo and Sarah Bertelsen and Anthony Hinrichs and Fagan, {Anne M.} and Holtzman, {David M.} and Morris, {John C.} and Goate, {Alison M.}",
note = "Funding Information: Data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec, Inc.; Bristol-Myers Squibb Company; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innoge-netics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Servier; Synarc, Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih. org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the Rev August 16 2011 University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514 and the Dana Foundation. Funding Information: This work was supported by Pfizer and grants from the National Institutes of Health (P30-NS069329-01, R01-AG035083, P50 AG05681) and the Alzheimer{\textquoteright}s Association (MNIRG-11-205368). Some of the samples used in this study were gen-otyped by the ADGC and GERAD. ADGC is supported by grants from the NIH (#U01AG032984) and GERAD from the Wellcome Trust (GR082604MA) and the Medical Research Council (G0300429).",
year = "2012",
month = oct,
doi = "10.1093/hmg/dds296",
language = "English",
volume = "21",
pages = "4558--4571",
journal = "Human Molecular Genetics",
issn = "0964-6906",
number = "20",
}