Abstract Body

The APOE4 allele increases the risk of Alzheimer's disease (AD). Similarly, low plasma apolipoprotein E (apoE) levels increase the risk of AD and other types of dementia. Plasma apoE levels, mainly derived from the liver, are known to vary in an APOE genotype-dependent manner however our recent results suggest that this effect may vary between ethnicities. Plasma apoE cannot cross the blood-brain-barrier, nevertheless our results expose an unfavorable association between low plasma apoE levels, cognition and cerebrospinal fluid (CSF) AD biomarkers. Recent results further propose that plasma apoE levels are linked to plasma glucose but not insulin levels which may help explain why a higher relative ratio of the apoE4 isoform over apoE3 in cognitively healthy APOE3/4 carriers was associated with glucose hypometabolism and gray matter volume reductions in AD relevant brain areas. Furthermore, APOE4-carriers exhibit higher plasma triglyceride levels and plasma apoE4 was positively correlated with plasma levels of total cholesterol and low-density lipoprotein. With the liver as an essential player in the peripheral glucose and lipid metabolism we are investigating a potential liver-phenotype which could explain the APOE4-promoted risk of AD. Our preliminary results suggest altered hepatic protein levels mainly of the amyloid-beta degrading enzyme cathepsin-D in an APOE4-dependent manner, and we speculate in line with other recent studies that altered hepatic amyloid-beta metabolism may be linked to AD brain pathology. Our ongoing lipidomic profiling of primary human hepatocytes from APOE4 versus non-APOE4 carriers will further aid our efforts of finding an APOE4 liver phenotype that drives the increased risk of AD.