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

Carlos Cruchaga, John S.K. Kauwe, Petra Nowotny, Kelly Bales, Eve H. Pickering, Kevin Mayo, Sarah Bertelsen, Anthony Hinrichs, Anne M. Fagan, David M. Holtzman, John C. Morris, Alison M. Goate

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

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).

Original languageEnglish
Article numberdds296
Pages (from-to)4558-4571
Number of pages14
JournalHuman molecular genetics
Volume21
Issue number20
DOIs
StatePublished - Oct 2012

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