[P3–106]: CHASING THE CAUSE OF PLASMA APOE DEFICIENCY IN THE LIVERS OF APOEε4 CARRIERS

The strongest risk-determinant for the development of sporadic Alzheimer's disease (AD) is the polymorphic APOE gene. In humans APOE has three variants, APOEε2, APOEε3 and APOEε4 whereof the latter increases the risk of disease 4–15 fold in a dose-dependent manner whilst APOEε2 appears to be protective. The biological mechanisms underlying the modified risk of disease in APOEε2 and APOEε4 carriers are not known. We previously showed that APOEε4-carriers exhibit a prominent plasma apolipoprotein E (apoE) deficiency caused by a specific reduction of the apoE4 isoform. This apoE deficiency was not observed in cerebrospinal fluid. In cognitively intact APOEε3/ε4 carriers an increased relative ratio of plasma apoE4 to apoE3 correlated to glucose hypometabolism and gray matter volume reductions in brain areas most often affected in AD. Hence, we speculate that peripheral apoE levels are linked to processes driving the risk of developing AD brain pathology. In order to determine the cause of the observed phenotype of plasma apoE deficiency in APOEε4-carriers we aimed to investigate the expression of different APOE alleles in liver biopsies from individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. Liver biopsies from liver explants were received from n=3 APOEε3/ε4 and n=3 APOEε2/ε3 carriers who had undergone liver transplantation at the Karolinska University Hospital in Sweden. Total RNA (≥80% in DV200 score) was isolated according to routine laboratory methods and used for RNA sequencing employing the high-throughput Illumina platform. Paired-end sequencing reads were aligned to the human reference genome (hg19), using TopHat, and gene counts for expression determined using HTseq-count. Differential expression between the genotype groups was calculated using DEseq2. Preliminary analyses revealed differential expression of n=624 genes between individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. In total n=624 genes are differentially expressed in livers from APOEε3/ε4 versus APOEε2/ε3 carriers. Further analyses will reveal the identity of the differentially expressed genes and whether there is a specific difference in the expression of APOE alleles that could explain the observed APOEε4 related plasma apoE deficiency