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Inheritance of the apolipoprotein E (APOE) epsilon 4 allele is associated with an increased risk of Alzheimer's disease (AD). However, the risk of AD in APOE epsilon 3/ epsilon 4 heterozygotes is variable. We tested the hypothesis that the risk of AD in APOE epsilon 3/ epsilon 4 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 epsilon 3/epsilon 3 homozygotes and were comparable to the total apoE ELISAs in APOE epsilon 4/ epsilon 4 homozygotes. In APOE epsilon 3/ epsilon 4 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 epsilon 3/epsilon 4 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.

Our studies of the APOE genotype in AD confirm a strong association of the epsilon 4 allele with development of AD and a decreased risk associated with epsilon 2. From a clinical/neuropathological perspective, the major effects of APOE epsilon 4 are to lower the age of onset and to increase the amount of A beta deposit in the brain. Neither rate of progression nor number of neurofibrillary tangles were affected. We also carried out a longitudinal population-based assessment of the APOE genotype to determine the risk for developing cognitive impairment of someone in the general population based on APOE genotype. APOE epsilon 4 carried about 1.4-fold increased risk, and APOE epsilon 2 about 1.7-fold decreased risk. Thus, inheritance of APOE epsilon 4 is a major biological risk factor for AD, but it has limited utility as a prognostic indicator for development of dementia in an individual.