P1‐224: APOE Genotype is Associated with Cerebrospinal Fluid and Plasma APOE Levels But Not with APOE Expression Levels

Apolipoprotein E (APOE)genotype is the strongest genetic risk factor for late-onset Alzheimer'sdisease (LOAD). APOE protein levels can be measured in the cerebrospinal fluid (CSF) and plasma. Previous studies have failed to detect an association between APOE genotype and CSF levels of APOE. In this project, we tested whether APOE genotype or other variants in the APOE-TOMM40 region are associated with either CSF or plasma APOE levels. APOE protein levels in the cerebrospinal fluid and plasma were quantified using the Luminex xMAP Multiplexing Technology in 349 samples. Expression studies were carried out using cDNA obtained from the parietal lobes of 82 AD cases and 39 cognitively normal individuals (CDR = 0). The SNPs that determine APOE genotype and 20 other SNPs in the APOE-TOMM40 region were genotyped by TaqMan or KASpar technology. In our dataset, CSF and plasma APOE levels are not significantly correlated (R=0.10;p = 0.08), however APOE genotype is strongly associated with both CSF (R=0.14; p = 2.4x10) and plasma APOE levels (R=0.26; p = 2.4x10). No association was found with any other genotyped SNP in the APOE-TOMM40 region when APOE genotype was included as covariate in the model. No association between APOE genotype and APOE mRNA expression was found (R=0.05; p = 0.28). We confirmed that APOE genotype is associated with plasma APOE protein levels and failed to observe evidence for any other variation in this region influencing plasma APOE. In contrast to previous results we also observed a strong association between APOE genotype and APOE protein levels in CSF. This may be due to sample size or differences in the ELISA used to measure APOE levels. We did not find an association with APOE gene expression levels. The differences in APOE protein levels in CSF may be due to differences in APOE clearance or degradation resulting from differences in affinity of the APOE isoforms for its receptor.