Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels

Abstract

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.

Fig. 1. APOE ε4, gender, age and CSF apoE levels

There is no significant difference in CSF apoE levels between APOE genotypes (Panel A) or between the presence or absence of APOE ε4 (Panel B). There is not a significant difference in CSF apoE levels between genders (Panel C). There is a significant increase in CSF apoE with increasing age (Panel D).

Fig. 2. CSF apoE mean levels

Bars represent CSF apoE means for variant or non-variant carrier groups for each SNP after taking into account age. Error bars represent standard error and n equals the number of individuals within the group analyzed. SNPs found to predict CSF apoE levels in backward regression models shown in Table 3 are designated with a *. SNPs found to predict CSF apoE levels after taking into account age and other SNPs (n17664883 p-value, 0.002: rs449647 p-value, 0.088, n17684509 p-value, 0.021) are designated with a #.