Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimers disease

The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimers 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 A(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF A(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 A(42) levels was independent of the APOE ?4 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 ?4 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 ?4 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)).