APOE ε3/ε4 heterozygotes have an elevated proportion of apolipoprotein E4 in cerebrospinal fluid relative to plasma, independent of Alzheimer's disease diagnosis

Inheritance of the apolipoprotein E (APOE) epsilon4 allele is associated with an increased risk of Alzheimer's disease (AD). However, the risk of AD in APOE epsilon3/epsilon4 heterozygotes is variable. We tested the hypothesis that the risk of AD in APOE epsilon3/epsilon4 heterozygotes was linked to the relative levels of expression of apoE4 versus apoE3 protein. We measured the apoE4 isoform and total apoE using two specific enzyme-linked immunosorbent assay (ELISA) kits in three cohorts of plasma samples and two cohorts of cerebrospinal fluid samples from AD, mild cognitive impairment, and control subjects. The apoE4 ELISAs were specific as they did not detect apoE in APOE epsilon3/epsilon3 homozygotes and were comparable to the total apoE ELISAs in APOE epsilon4/epsilon4 homozygotes. In APOE epsilon3/epsilon4 individuals, the ratio of apoE4 to total apoE levels was 30-40% in plasma, suggesting a decreased production or an increased metabolism of apoE4 compared to apoE3. Surprisingly, the ratio in the CSF was reversed, with apoE4 accounting for 60-70% of the total apoE. The proportion of apoE4 in these cases did not vary by diagnosis, age of onset, or duration of AD. We conclude that the proportion of apoE4 in plasma is not predictive of AD risk in APOE epsilon3/epsilon4 individuals. However, the greater proportion of apoE4 in the cerebrospinal fluid suggests differential production or metabolism of the protein in the central nervous system (CNS), with the apoE4 isoform dominating. (C) 2003 Elsevier Science (USA). All rights reserved.