Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1 polymorphisms

Abstract

Background: Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-beta (Abeta) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs).

Results: In all subjects, the mean CSF apoE level was 9.09 microg/ml with a standard deviation of 2.70 microg/ml. Levels of apoE in CSF samples taken from the same individual two weeks apart were strongly correlated (r2 = 0.93, p < 0.01). In contrast, CSF apoE levels in different individuals varied widely (coefficient of variation = 46%). CSF apoE levels did not vary according to AD status, APOE genotype, gender or race. Average apoE levels increased with age by approximately 0.5 microg/ml per 10 years (r2 = 0.05, p = 0.003). We found no significant associations between CSF apoE levels and the ten ABCA1 SNPs we genotyped. Moreover, in a separate sample of 1225 AD cases and 1431 controls, we found no association between the ABCA1 SNP rs2230806 and AD as has been previously reported.

Conclusion: We found that CSF apoE levels vary widely between individuals, but are stable within individuals over a two-week interval. AD status, APOE genotype, gender and race do not affect CSF apoE levels, but average CSF apoE levels increase with age. Given the lack of association between CSF apoE levels and genotypes for the ABCA1 SNPs we examined, either these SNPs do not affect ABCA1 function or if they do, they do not have strong effects in the CNS. Finally, we find no evidence for an association between the ABCA1 SNP rs2230806 and AD in a large sample set.

Figure 1

Distribution of apoE levels in human CSF. A, ApoE levels were sorted into bins of 1 μg/ml and the number of subjects with apoE values within each bin was tallied. The data represents 168 subjects without division by CDR status, APOE genotype, gender, race or age. B, ApoE levels were measured in CSF samples taken two weeks apart from five different patients.

Figure 2

ApoE levels in human CSF do not vary according to presence or absence of Alzheimer's disease, level of cognitive impairment, APOE genotype, gender or race, but do increase with age. A, Subjects were grouped by age and AD status. Subjects with a clinical dementia rating (CDR) score of 0 (cognitively normal) that were less than age 65 were placed into the first group (CDR 0, <65; n = 59). Subjects that were 65 and older with a CDR score of 0, 0.5, or 1–2 were placed into the second (CDR 0, n = 50), third (CDR 0.5, n = 21) and fourth (CDR 1+, n = 14) groups, respectively. There was no difference in CSF apoE levels by one-way ANOVA. B, Subjects were grouped by APOE genotype into four groups: E2/E3 (n = 23), E3/E3 (n = 72), E3/E4 (n = 52), and E4/E4 (n = 9). There was no difference in CSF apoE levels by one-way ANOVA. C, Subjects were divided into two groups, female (n = 109) and male (n = 57). There was no difference in CSF apoE levels by a two-tailed Student's T-test. D, Subjects were grouped by self-identified racial group: African American (n = 17) and Caucasian (n = 149). There was no difference in CSF apoE levels by a two-tailed Student's T-test. E, CSF apoE levels were graphed as a function of subject age (n = 168). The slope of the regression line was 0.05, with a 95% confidence interval of 0.02 to 0.08.